Long acting gastric residence system

ABSTRACT

Provided herein are gastroretentive dosage forms (GRDFs) for extended retention in a human stomach, comprising a body comprising at least two arms, the body configured to transform between a collapsed configuration for ingestion, an expanded configuration for retention within the stomach and a disassembled configuration wherein after a predetermined time period has elapsed, the GRDF disassembles into at least two parts such that each of the disassembled parts of the GRDF is sized for exiting the stomach; and, an erodible insert comprising a therapeutic agent, a diagnostic agent, an electronical device, or a combination thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 16/769,046, filedJun. 2, 2020, which is the National Stage Application of InternationalPatent Application No. PCT/IB2018/059579, filed Dec. 3, 2018, whichclaims the benefit of U.S. provisional application No. 62/594,257 filedDec. 4, 2017, and U.S. provisional application No. 62/681,525 filed Jun.6, 2018, the entire disclosures of each of which are incorporated hereinby reference.

TECHNICAL FIELD

The present disclosure relates to a pharmaceutical product or system.More particularly, the present disclosure relates to gastric residencesystems or gastroretentive dosage forms (GRDF) useful for extendedretention of therapeutic agents, diagnostic agents and/or electronicdevices in the stomach.

BACKGROUND

Gastric residence systems (GRS) are delivery systems which remain in thestomach for extended periods of time. They enable oral delivery of anactive pharmaceutical ingredient (API), diagnostic or electronic deviceetc. to the gastrointestinal (GI) tract, for example for the purpose ofextended GI residence, for local treatment of the upper GI, forcontinuous exposure of API especially those with a narrow absorptionwindow or low solubility in the intestine. Gastric residence systemsfall within three areas of technology: namely floating systems,bio-adhesives and systems with expanding geometry through swelling orunfolding.

Folding systems are conveniently administered to a patient in a foldedor compacted form for example via a capsule. Once in the stomach,dissolution of the capsule in the stomach results in the systemexpanding or unfolding to a size which resists passage through thepyloric sphincter over the desired residence period. Examples of suchsystems are described in the following publications: U.S. Pat. No.4,735,804, PCT/US2015/033850, PCT/US2015/035423 and PCT/IB2011/002888.

Requirements for folding systems include providing a safe andpharmaceutically acceptable system which is compact for swallowing, ableto unfold to an effective expanded system that can endure themechanically and chemically harsh environment of the stomach for adesired residence period and eventually exit the stomach safely and in atimely manner. The present disclosure describes advancements in thedesign of improved structures for extended residence in the stomach.

To date, there are no approved products for oral delivery to the humanupper gastro-intestinal tract and specifically to the stomach whichrelease active agents for more than 24 hours.

A gastric retentive product having the ability to retain therapeutic ordiagnostic agents, and/or electronic devices in the stomach over atleast about 48 hours, at least about 3 days, at least about 4 days, atleast about 5 days, at least about 6 days, at least about 7 days or atleast about 8 days is desired.

SUMMARY

Aspects of the invention are defined herein below and in theaccompanying claims.

The subject invention provides a gastroretentive dosage form (GRDF) forextended retention in a human stomach, comprising:

a body comprising at least two arms, the body configured to transformbetween a collapsed configuration for ingestion, an expandedconfiguration for retention within the stomach and a disassembledconfiguration wherein after a predetermined time period has elapsed, theGRDF mechanically disassembles into at least two parts such that each ofthe disassembled parts of the GRDF is sized for exiting the stomach; andan erodible insert comprising a therapeutic agent, a diagnostic agent,an electronical device, or a combination thereof;wherein the disassembled configuration is induced by at least partialerosion of the erodible insert, and wherein the GRDF is adapted to beretained in the stomach for at least 3 days, at least 4 days, at least4.7 days, at least 5 days, at least 6 days, at least 6.6 days, at least7 days, at least 8 days, or at least 8.3 days.

The subject invention also provides a mechanism for priming of a GRDFfor administering to a patient, the GRDF comprising:

a body including at least two arms, the body configured to transformbetween a collapsed configuration for ingestion, an expandedconfiguration for retention within the stomach and a disassembledconfiguration, wherein after a predetermined time period has elapsed,the GRDF disassembles into at least two parts such that each of thedisassembled parts of the GRDF is sized for exiting the stomach,an erodible insert comprising a therapeutic agent, a diagnostic agent,an electronical device, or a combination thereof;a biasing member having a first portion and a second portion;a retainer configured to house the GRDF for ingestion, wherein theretainer has a main portion and a closing portion, wherein the retaineris configured to retain the GRDF in the collapsed configuration; anda priming member extending from an interior side of said closing portionof the retainer,and further comprising the steps of:locating said GRDF in said main portion, wherein the GRDF is in acollapsed configuration;attaching the closing portion to the main portion of the retainer;pressing the closing portion in the direction of the main body so thatsaid priming member pushes said first portion of the biasing member to aposition perpendicular to said second portion of the priming biasing;thereby priming the GRDF for administering to the patient.

The subject invention also provides a GRDF comprising a body, the bodycomprising at least two arms and configured to transform between acollapsed configuration for ingestion, an expanded configuration forretention within the stomach and a disassembled configuration, whereinafter a predetermined time period has elapsed, the GRDF disassemblesinto at least two parts such that each of the disassembled parts of theGRDF is sized for exiting the stomach; an erodible insert comprising atherapeutic agent, a diagnostic agent, an electronical device, or acombination thereof; a biasing member; and at least one hinge assembly,wherein the biasing member and the at least one hinge assembly areconnected by an elastic element.

The subject invention also provides a method of preparing agastroretentive dosage form (GRDF) comprising:

providing material for injection molding, optionally agastric-non-erodible polymer;injection molding a first, a second and a third arm;optionally coating one or more arm(s) with a gastric-non-erodiblecoating;inserting an erodible insert comprising a therapeutic agent, adiagnostic, an electronic device, or combination thereof, into saidfirst arm;connecting said first, second and third arms in the form of a triangle;andoptionally compressing said triangular shaped system into a retainer.

The subject invention also provides a GRDF for extended retention in ahuman stomach, the GRDF comprising:

a body comprising at least two arms, the body configured to transformbetween a collapsed configuration for ingestion, an expandedconfiguration for retention within the stomach and a disassembledconfiguration wherein after a predetermined time period has elapsed, theGRDF mechanically disassembles into at least two parts such that each ofthe disassembled parts of the GRDF is sized for exiting the stomach; andan erodible insert comprising a therapeutic agent, a diagnostic agent,an electronical device, or a combination thereof wherein the erodibleinsert has two opposing ends;wherein the GRDF further comprises a retainer surrounding the GRDF andconfigured to retain the GRDF in the collapsed configuration; whereintransformation of the GRDF from the collapsed configuration to theexpanded configuration is induced by erosion of the retainer; wherein atleast a portion of at least one arm of said at least two arms forms asleeve, tube or shell, wherein the sleeve, tube or shell of said atleast one arm comprises a cavity, the cavity housing the erodibleinsert; wherein said sleeve, tube or shell of said at least one armincludes at least one opening configured to allow penetration of gastricfluid into the cavity, wherein an uncoated surface area on said erodibleinsert overlaps with said at least one opening in said sleeve, tube orshell thereby defining at least one overlapping area which is exposed togastric fluid; wherein erosion of the erodible insert progresses fromthe at least one overlapping area towards said two opposing ends of saiderodible insert, and wherein the disassembled configuration of the GRDFis induced by at least 70% (w/w) erosion of said erodible insert.

The subject invention also provides an erodible insert configured to becontained in a GRDF, wherein the erodible insert comprises a therapeuticagent, a diagnostic agent, an electronical device, or a combinationthereof, wherein the GRDF comprises said erodible insert and a bodycomprising at least two arms, the body configured to transform between acollapsed configuration for ingestion, an expanded configuration forretention within the stomach and a disassembled configuration, whereinafter a predetermined time period has elapsed, the GRDF disassemblesinto at least two parts such that each of the disassembled parts of theGRDF is sized for exiting the stomach, wherein the disassembledconfiguration is induced by at least partial erosion of said erodibleinsert, wherein at least a portion of at least one arm of said at leasttwo arms forms a sleeve, tube or shell, wherein said sleeve, tube orshell comprises a cavity, wherein the cavity is configured to house theerodible insert, wherein the erodible insert is contained in the cavity,wherein the erodible insert is partially coated with agastric-non-erodible coating. The subject invention also provides amethod of delivering a therapeutic agent, a diagnostic, an electronicdevice, or combination thereof to the stomach of a subject for anextended period of time comprising: providing a GRDF according to thepresent invention, wherein at least one of the arms houses an erodibleinsert comprising a therapeutic agent, a diagnostic, an electronicdevice, or combination thereof.

The subject invention also provides a method of delivering a therapeuticagent, a diagnostic, an electronic device, or combination thereof to thestomach of a subject for an extended period of time comprising:administering a GRDF according to the present invention to a patient.

BRIEF DESCRIPTION OF THE DRAWINGS

The teachings of the present disclosure will now be described by way ofexample only with reference to the following drawings in which likeparts are depicted by like reference numerals:

FIGS. 1A and 1B are schematic front views of a GRDF in an expandedconfiguration;

FIG. 2A is a cross sectional view of an erodible insert contained withinan arm of the GRDF of FIGS. 1A and 1B;

FIG. 2B is a schematic front view of the GRDF of FIGS. 1A and 1Billustrating the erodible insert located within the system;

FIGS. 3A and 3B are simplified drawings of the GRDF of FIGS. 1A and 1B;

FIG. 3C is a simplified drawing of the hyphenated area in FIG. 3B;

FIG. 4A is a front view of the GRDF of FIGS. 1A and 1B in a compressedconfiguration;

FIG. 4B is a simplified drawing of FIG. 4A;

FIG. 4C is a vertically distorted version of FIG. 4B;

FIG. 5 is a simplified drawing of the transition of a GRDF from acompressed state to an expanded state;

FIG. 6 is a flow chart of the process which a GRDF undergoes in use;

FIGS. 7A-7D illustrate a sequence of simplified drawings showing thechange in an erodible insert within the GRDF of FIGS. 1A-1B over time;

FIG. 8 is a simplified drawing of the GRDF of FIGS. 1A-1B in use;

FIGS. 9A-9C illustrate simplified drawings of the expanded state and twoalternative disassembled states of the GRDF of FIGS. 1A-1B;

FIG. 10 is a front view of a GRDF in an expanded configuration;

FIG. 11 is a cross-sectional view of the GRDF of FIG. 10 ;

FIGS. 12 a-12 c illustrate close up views of a locking mechanism of theGRDF of FIG. 10 ;

FIG. 13 illustrates a close up view of a guiding or sliding mechanism ofthe GRDF of FIG. 10 ;

FIG. 14A is a front view of the GRDF of FIG. 10 in a compressedconfiguration;

FIG. 14B is a cross-sectional view of the GRDF of FIG. 10 in acompressed configuration;

FIGS. 15A-15D are cross-sectional views illustrating the disassembly ofthe GRDF of FIG. 10 ;

FIGS. 16A-16C are cross-section views of alternative arrangements of abiasing element of the GRDF of FIG. 10 ;

FIG. 17 is a front view of an alternative GRDF in an expandedconfiguration;

FIGS. 18A-18C are x-ray imaging photographs of an exemplary residencestructure according to one example in the GI of a human subject;

FIGS. 19A and 19B illustrate arms and hinge assemblies of the GRDF shownin FIG. 10 ;

FIGS. 19C and 19D illustrate views of a sleeve of the GRDF shown in FIG.10 ;

FIGS. 20A-20D illustrate a method of measuring the opening force viacalculation of a minimum force applied to the GRDF in the compressedstate which prevents opening as well as a measure of the rigidity ofstructure under a compression force applied to the apex of the GRDF inthe expanded state of a comparative example and the present GRDFdisclosed herein;

FIG. 21A is a top (T) and bottom (B) view, FIG. 21B is a 3 dimensionalside view of the sleeve with holes, and FIG. 21C presents the surfacearea in mm² of exposing holes R1-R5. S is small, M is medium and L islarge;

FIG. 22 is a cross-sectional view of the GRDF with the additionaldisplay of the coated erodible and openings 2007 at the top and bottomof the tube, the tablets are coated with a gastric-non-erodible coatingon the surfaces that are not in contact with another tablet or with a2007 opening;

FIG. 23 is a graph displaying the results of Example 7a as a percentrelease of a therapeutic agent (Entacapone) over time in days asmeasured in rotating bottle apparatus at 37° C. at 2.5 RPM having 400mL, pH2 and Xanthan gum 0.125 gr/L;

FIG. 24 is a graph displaying the results of Examples 7b, 7c and 7d as apercent release of therapeutic agents (Levodopa and Carbidopa) over timein days as measured in rotating bottle apparatus at 37° C. at 2.5 RPMhaving 400 mL, pH2 and Xanthan gum 0.125 gr/L;

FIG. 25 is a cross-section view of the GRDF including an elastic elementin the compressed and expanded configurations;

FIG. 26 illustrates arrangements of the elastic element in thecompressed and expanded configurations of the GRDF and activity upondissolution of the retainer.

While the invention is susceptible to various modifications andalternative forms, specific embodiments are shown by way of example inthe drawings and are herein described in detail. It should beunderstood, however, that the drawings and detailed description of thespecific embodiments are not intended to limit the invention to theparticular forms disclosed. On the contrary, the invention is intendedto cover all modifications, equivalents and alternatives falling withinthe spirit and scope of the present invention as defined by the appendedclaims.

DETAILED DESCRIPTION

The present disclosure is in the field of gastroretentive dosage forms.A gastroretentive dosage form for extended retention in a stomach isprovided.

The following numbered clauses define various aspects and features ofthe present invention:

-   -   1. A gastroretentive dosage form (GRDF) for extended retention        in a human stomach, comprising:        -   a. a body comprising at least two arms, the body configured            to transform between a collapsed configuration for            ingestion, an expanded configuration for retention within            the stomach and a disassembled configuration wherein after a            predetermined time period has elapsed, the GRDF mechanically            disassembles into at least two parts such that each of the            disassembled parts of the GRDF is sized for exiting the            stomach; and        -   b. an erodible insert comprising a therapeutic agent, a            diagnostic agent, an electronical device, or a combination            thereof;    -   wherein the disassembled configuration is induced by at least        partial erosion of the erodible insert, and wherein the GRDF is        adapted to be retained in the stomach for at least 3 days, at        least 4 days, at least 4.7 days, at least 5 days, at least 6        days, at least 6.6 days, at least 7 days, at least 8 days, or at        least 8.3 days.    -   2. The GRDF according to clause 1, wherein the GRDF further        comprises a retainer configured to retain the GRDF in the        collapsed configuration.    -   3. The GRDF according to clause 2, wherein transformation of the        GRDF from the collapsed configuration to the expanded        configuration is induced by erosion of the retainer.    -   4. The GRDF according to any of clauses 2-3, wherein the        retainer is selected from a capsule, a wrapper, or band        surrounding the GRDF.    -   5. The GRDF according to any of clauses 1-4, wherein the body        comprises at least three arms.    -   6. The GRDF according to any of clauses 1-5, wherein the body        comprises three arms.    -   7. The GRDF according to any of clauses 1-6, wherein the body        further comprises at least one hinge assembly configured to        disengage from at least one arm upon at least partial erosion of        the erodible insert.    -   8. The GRDF according to any of clauses 1-7, wherein the at        least partial erosion of the erodible insert is at least 70%        (w/w), at least 80% (w/w), at least 87% (w/w), at least 90%        (w/w), at least 95% (w/w), at least 98% (w/w) or about 100%        (w/w) erosion of the initial weight of the erodible insert.    -   9. The GRDF according to any of clauses 1-8, wherein at least a        portion of at least one arm forms a sleeve, tube or shell.    -   10. The GRDF according to any of clauses 1-9, wherein at least        one arm of the at least two arms forms a sleeve, tube or shell.    -   11. The GRDF according to any of clauses 9-10, wherein the        sleeve, tube or shell comprises a cavity.    -   12. The GRDF according to clause 11, wherein the cavity is        configured to house the erodible insert.    -   13. The GRDF according to clause 12, wherein the erodible insert        is contained in the cavity.    -   14. The GRDF according to any of clauses 1-13, wherein the        erodible insert is partially coated with a gastric-non-erodible        coating.    -   15. The GRDF according to any of clauses 9-14, wherein the        sleeve, tube or shell comprises at least one opening configured        to allow penetration of gastric fluid into the cavity.    -   16. The GRDF according to any of clauses 1-15, wherein the GRDF        comprises at least two arms, wherein at least a portion of at        least one arm of said at least two arms forms a sleeve, tube or        shell, wherein the sleeve, tube or shell of said at least one        arm comprises a cavity, wherein said cavity is configured to        house an erodible insert, wherein said erodible insert is housed        in said cavity, wherein said sleeve, tube or shell includes at        least one opening configured to allow penetration of gastric        fluid into the cavity, wherein an uncoated surface area on said        erodible insert overlaps with said at least one opening in said        sleeve, tube or shell, thereby defining at least one overlapping        area which is exposed to gastric fluid.    -   17. The GRDF according to clause 16, wherein a sum area of the        at least one overlapping area is about 15.5 to about 59.8 mm².    -   18. The GRDF according to clause 16, wherein the sum area of the        at least one overlapping areas is less than 59.8 mm², or less        than 40.7 mm², or less than 15.5 mm².    -   19. The GRDF according to clause 18, wherein the sum area of the        at least one overlapping area is less than 59.8 mm² and the        gastric retention time is at least 4.6 days, or the sum area of        the at least one overlapping area is less than 40.7 mm² and the        gastric retention time is at least 6.6 days, or the sum area of        the at least one overlapping area is less than 15.5 mm² and the        gastric retention time is at least 8.3 days.    -   20. The GRDF according to any of clauses 1-19 wherein the        erodible insert is an elongate erodible insert having two        opposing ends.    -   21. The GRDF according to any of clauses 16-20, wherein the GRDF        includes one overlapping area.    -   22. The GRDF according to clauses 16-20, wherein the GRDF        includes two or more overlapping areas.    -   23. The GRDF according to any of clauses 16-22, wherein the at        least one overlapping area is equidistant from both ends of the        erodible insert or ends of the arm.    -   24. The GRDF according to any of clauses 16-23, wherein the at        least one overlapping area is located closer to one end of the        erodible insert than to the other end of the erodible insert.    -   25. The GRDF according to any of clauses 21-24 wherein erosion        of the erodible insert progresses bidirectionally from the        overlapping area to both ends of the erodible insert.    -   26. The GRDF according to any of clauses 1-25, wherein at least        70% (w/w), at least 80% (w/w), at least 87% (w/w), at least 90%        (w/w), at least 95% (w/w), at least 98% (w/w) or about 100%        (w/w) of the initial weight of the therapeutic agent is released        prior to GRDF disassembly.    -   27. The GRDF according to any of clauses 1-26, wherein less than        20% (w/w), less than 10% (w/w), or less than 5% (w/w) of the        GDRF body weight is eroded by gastric fluid or simulated gastric        fluid.    -   28. The GRDF according to any of clauses 1-26, wherein less than        20% (w/w), less than 10% (w/w), or less than 5% (w/w) of the        weight of the at least two arms and the at least one hinge        assembly is eroded by gastric fluid or simulated gastric fluid.    -   29. The GRDF according clause 28, wherein the at least two arms        and the at least one hinge assembly substantially retain their        original size, shape and/or weight in the presence of gastric        fluid or simulated gastric fluid.    -   30. The GRDF according to any of clauses 8 or 26-29, wherein %        release (w/w) or % erosion (w/w) is measured using simulated        gastric conditions in a rotating bottle apparatus at 37° C. at        2.5 RPM having 400 mL, pH2 and Xanthan gum 0.125 gr/L.    -   31. The GRDF according to any of clauses 1-30, wherein the        erodible insert comprises at least 1, at least 2, at least 3, at        least 4 or at least 5 tablets.    -   32. The GRDF according to clause 31, wherein the erodible insert        consists of 1, 2, 3, 4 or 5 tablets.    -   33. The GRDF according to clause 32, wherein the erodible insert        consists of 4 tablets or wherein the erodible insert consists of        5 tablets.    -   34. The GRDF according to clause 33, wherein at least one tablet        comprises a therapeutic agent.    -   35. The GRDF according to any of clauses 31-34, wherein each        tablet comprises a therapeutic agent.    -   36. The GRDF according to any of clauses 31-34, wherein at least        one tablet comprises more than one therapeutic agent.    -   37. The GRDF according to any of clauses 31-36, wherein at least        one tablet is at least partially coated with a        gastric-non-erodible coating.    -   38. The GRDF according to clause 37, wherein each tablet is at        least partially coated with a gastric-non-erodible coating.    -   39. The GRDF according to any of clauses 1-38, wherein the        erodible insert comprises more than one therapeutic agent.    -   40. The GRDF according to any of clauses 1-39, wherein the        erodible insert is not fastened to the body of the GRDF by a        physical measure selected from gluing or tethering.    -   41. The GRDF according to any of clauses 1-40, wherein the        erodible insert is not fastened to the at least two arms by a        physical measure selected from gluing or tethering.    -   42. The GRDF according to any of clauses 1-41, wherein the at        least two arms and/or the at least one hinge assembly do not        comprise an elastomer.    -   43. The GRDF according to any of clauses 1-42, wherein the at        least two arms and/or the at least one hinge assembly are coated        with a gastric-non-erodible coating.    -   44. The GRDF according to any of clauses 1-43, wherein the body        consists of gastric-non-erodible materials.    -   45. The GRDF according to any of clauses 1-43, wherein the at        least two arms and/or the at least one hinge assembly consists        of gastric-non-erodible material.    -   46. The GRDF according to any of clauses 44-45, wherein the        gastric-non-erodible materials are at least one        gastric-non-erodible polymer.    -   47. The GRDF according to clause 46, wherein the at least one        gastric-non-erodible polymer is cellulose ester.    -   48. The GRDF according to clause 47, wherein the cellulose ester        is selected from cellulose acetate, cellulose butyrate, or a        combination thereof.    -   49. The GRDF according to any of clauses 1-48, wherein the body        is composed of material that does not comprise a therapeutic        agent.    -   50. The GRDF according to any of clauses 1-48, wherein the body        is composed of material that is not eroded in gastric fluid or        simulated gastric fluid, or at GRDF disassembly.    -   51. The GRDF according to any of clauses 1-48, wherein the at        least two arms and the at least one hinge assembly are composed        of material that does not erode in gastric fluid or simulated        gastric fluid, or at GRDF disassembly.    -   52. The GRDF according to any of clauses 1-51, wherein the        erodible insert is configured to erode upon contact with gastric        fluid or simulated gastric fluid.    -   53. The GRDF according to clause 52, wherein erosion of the        erodible insert is configured to release the therapeutic agent,        diagnostic agent, electronic device or combination thereof into        the gastric fluid.    -   54. The GRDF according to any of clauses 1-53, wherein the at        least two arms comprise a first arm, a second arm and a third        arm.    -   55. The GRDF according to clause 54, the first arm comprising a        first end and a second opposing end, the second and third arms        being pivotally connected to the first end and the second end of        the first arm, respectively.    -   56. The GRDF according to any of clauses 54-55, comprising a        biasing member configured to bias the GRDF into the expanded        configuration, wherein in the expanded configuration, the second        and third arms are configured to mechanically engage each other        to retain the GRDF in the expanded configuration.    -   57. The GRDF according to any of clauses 54-56, wherein a        portion of the second arm distal to the first arm and a portion        of the third arm distal to the first arm are configured to        mechanically engage each other in the expanded configuration.    -   58. The GRDF according to any of clauses 54-57, wherein the        third arm comprises a retaining surface against which the second        arm engages when the GRDF is in the expanded configuration.    -   59. The GRDF according to any of clauses 54-58, wherein the        third arm comprises a protrusion against which the second arm        engages when the GRDF is in the expanded configuration.    -   60. The GRDF according to clause 59, wherein the protrusion is        provided at an opposite end of the third arm to the first arm        and wherein in the expanded configuration, the end of the second        arm distal to the first arm engages with the protrusion to form        an apex.    -   61. The GRDF according to any of clauses 54-60, wherein during        transformation from the collapsed configuration to the expanded        configuration, an outer surface of the second arm is configured        to slide along the third arm.    -   62. The GRDF according to any of clauses 54-61, wherein the        third arm comprises an elongate protrusion along its length and        the second arm comprises a recess configured to cooperate with        the elongate protrusion during transformation from the collapsed        configuration to the expanded configuration.    -   63. The GRDF according to any of clauses 54-62, wherein in the        expanded configuration the first, second and third arms are        configured to form a generally triangular shape.    -   64. The GRDF according to clause 63, wherein a smallest turning        radius of the triangular shape is between 20 and 35 mm.    -   65. The GRDF according to any of clauses 54-64, wherein in the        collapsed configuration, the second arm is configured to overlay        the first arm and the third arm is configured to overlay the        second arm.    -   66. The GRDF according to any of clauses 54-65, wherein the        second and third arms are shaped such that an inner surface of        the third arm has a corresponding shape to an outer surface of        the second arm and an inner surface of the second arm has a        corresponding shape to an outer surface of the first arm.    -   67. The GRDF according to any of clauses 56-66, wherein the        biasing member comprises an elongate member configured to bias        the second arm.    -   68. The GRDF according to any of clauses 56-67, wherein the        second arm comprises a recess or protrusion configured to engage        a portion of the biasing member when the GRDF is in the expanded        configuration.    -   69. The GRDF according to any of clauses 56-68, wherein the        biasing member comprises at least one of an elastic leaf spring,        a helical spring attached to a rigid member and a superporous        hydrogel.    -   70. The GRDF according to any of clauses 54-69, wherein after a        predetermined time period in the expanded configuration, the        GRDF is configured to mechanically disassemble.    -   71. The GRDF according to clause 70, wherein the mechanical        disassembly of the GRDF comprises disconnection of the second        and/or third arms from the first arm.    -   72. The GRDF according to clause 71, wherein upon disconnection        of the second and/or third arms from the first arm, the second        and third arms are configured to disconnect from each other.    -   73. A mechanism for priming of a GRDF for administering to a        patient, the GRDF comprising:        -   a) a body including at least two arms, the body configured            to transform between a collapsed configuration for            ingestion, an expanded configuration for retention within            the stomach and a disassembled configuration, wherein after            a predetermined time period has elapsed, the GRDF            disassembles into at least two parts such that each of the            disassembled parts of the GRDF is sized for exiting the            stomach,        -   b) an erodible insert comprising a therapeutic agent, a            diagnostic agent, an electronical device, or a combination            thereof;        -   c) a biasing member having a first portion and a second            portion;        -   d) a retainer configured to house the GRDF for ingestion,            wherein the retainer has a main portion and a closing            portion, wherein the retainer is configured to retain the            GRDF in the collapsed configuration; and        -   e) a priming member extending from an interior side of said            closing portion of the retainer,            -   and further comprising the steps of:        -   i. locating said GRDF in said main portion, wherein the GRDF            is in a collapsed configuration;        -   ii. attaching the closing portion to the main portion of the            retainer;        -   iii. pressing the closing portion in the direction of the            main body so that said priming member pushes said first            portion of the biasing member to a position perpendicular to            said second portion of the priming biasing;            -   thereby priming the GRDF for administering to the                patient.    -   74. The mechanism according to clause 73, wherein the GRDF        further comprises a retaining element configured to retain the        biasing member in a primed state until dissolution of the        retainer.    -   75. The mechanism according to clauses 73-74, wherein the        retainer is a capsule, a wrapper, or band surrounding the GRDF.    -   76. A GRDF comprising a body, the body comprising at least two        arms and configured to transform between a collapsed        configuration for ingestion, an expanded configuration for        retention within the stomach and a disassembled configuration,        wherein after a predetermined time period has elapsed, the GRDF        disassembles into at least two parts such that each of the        disassembled parts of the GRDF is sized for exiting the stomach;        an erodible insert comprising a therapeutic agent, a diagnostic        agent, an electronical device, or a combination thereof; a        biasing member; and at least one hinge assembly, wherein the        biasing member and the at least one hinge assembly are connected        by an elastic element.    -   77. The GRDF according to clause 76, wherein the elastic element        is stretched when the GRDF is maintained in a collapsed        configuration.    -   78. The GRDF according to clause 77, wherein the elastic element        maintains its elastic properties with minimal to no plastic        deformation for at least 2 months, at least 4 months, at least        one year or at least 2 years.    -   79. The GRDF according to any of clauses 76-78, wherein the        elastic element comprises, or consists of, silicone rubber.    -   80. The GRDF according to any of clauses 76-79, wherein the        elastic element has a minimal tensile strength of 8.5 GPa and        minimal elongation of 500% as tested in ASTM D412.    -   81. The GRDF according to clause 80, wherein the elastic element        further has hardness of 40-80 shore A as tested in a D2240 ASTM        test.    -   82. The GRDF according to any of clauses 1-72 or 76-81, wherein        % release (w/w) of API out of the total initial API (w/w) per        day as measured over at least 3 days is about 10% to 25% (w/w),        or about 12% to 22% (w/w), or less than about 30% (w/w), or less        than about 25% (w/w), or less than about 20% (w/w), or less than        about 15% (w/w), or about 12% (w/w), as measured in vitro in a        rotating bottle apparatus at 37° C. at 2.5 RPM having 400 mL,        pH2 and Xanthan gum 0.125 gr/L.    -   83. The GRDF according to any of clauses 1-72 or 76-82, wherein        % RSD of the % release (w/w) of API out of the total API weight        per day as measured over at least 3 days is about 76%, or about        65%, or about 31%, or less than about 80%, or less than about        70% or less than about 50% or less than about 40% or less than        about 35%, as measured in vitro in a rotating bottle apparatus        at 37° C. at 2.5 RPM having 400 mL, pH2 and Xanthan gum 0.125        gr/L.    -   84. The GRDF according to any of clauses 1-72 or 76-83 wherein        the erodible insert comprises an extended-release excipient.    -   85. The GRDF according to clause 84, wherein the        extended-release excipient is methylcellulose, methocel or a        combination thereof.    -   86. A method of preparing a gastroretentive dosage form (GRDF)        comprising:        -   a. providing material for injection molding, optionally a            gastric-non-erodible polymer;        -   b. injection molding a first, a second and a third arm;        -   c. optionally coating one or more arm(s) with a            gastric-non-erodible coating;        -   d. inserting an erodible insert comprising a therapeutic            agent, a diagnostic, an electronic device, or combination            thereof, into said first arm;        -   e. connecting said first, second and third arms in the form            of a triangle; and        -   f. optionally compressing said triangular shaped system into            a retainer.    -   87. The method according to clause 86, further comprising:        -   a. injection molding a first and a second hinge assembly;        -   b. connecting the first arm to the second arm by said first            hinge assembly, and connecting the first arm to the third            arm by said second hinge assembly;        -   c. injection molding a biasing member;        -   d. connecting one of said first hinge assembly and said            second hinge assembly to said biasing member by an elastic            element.    -   88. The method according to clause 87, wherein the elastic        element is stretched when the GRDF is maintained in the        compressed configuration.    -   89. The method according to clause 88, wherein the elastic        element maintains its elastic properties with minimal to no        plastic deformation for at least 2 months, at least 4 months, at        least one year or at least 2 years.    -   90. The method according to any of clauses 87-89, wherein the        elastic element comprises, or is made of, silicone rubber.    -   91. The method according to any of clauses 87-90, wherein the        elastic element has a minimal tensile strength of 8.5 GPa and        minimal elongation of 500% as tested in ASTM D412.    -   92. The method according to clause 91, wherein the elastic        element further has hardness of 40-80 shore A as tested in a        D2240 ASTM test.    -   93. The method according to any one of clauses 86-92, wherein        all the materials are pharmaceutically acceptable.    -   94. A GRDF for extended retention in a human stomach, the GRDF        comprising:        -   a. a body comprising at least two arms, the body configured            to transform between a collapsed configuration for            ingestion, an expanded configuration for retention within            the stomach and a disassembled configuration wherein after a            predetermined time period has elapsed, the GRDF mechanically            disassembles into at least two parts such that each of the            disassembled parts of the GRDF is sized for exiting the            stomach; and        -   b. an erodible insert comprising a therapeutic agent, a            diagnostic agent, an electronical device, or a combination            thereof wherein the erodible insert has two opposing ends;        -   wherein the GRDF further comprises a retainer surrounding            the GRDF and configured to retain the GRDF in the collapsed            configuration; wherein transformation of the GRDF from the            collapsed configuration to the expanded configuration is            induced by erosion of the retainer; wherein at least a            portion of at least one arm of said at least two arms forms            a sleeve, tube or shell, wherein the sleeve, tube or shell            of said at least one arm comprises a cavity, the cavity            housing the erodible insert; wherein said sleeve, tube or            shell of said at least one arm includes at least one opening            configured to allow penetration of gastric fluid into the            cavity, wherein an uncoated surface area on said erodible            insert overlaps with said at least one opening in said            sleeve, tube or shell thereby defining at least one            overlapping area which is exposed to gastric fluid; wherein            erosion of the erodible insert progresses from the at least            one overlapping area towards said two opposing ends of said            erodible insert, and wherein the disassembled configuration            of the GRDF is induced by at least 70% (w/w) erosion of said            erodible insert.    -   95. The GRDF according to clause 94, wherein the disassembled        configuration of the GRDF is induced by at least 80% (w/w)        erosion of the erodible insert, by at least 87% (w/w) erosion of        the erodible insert, by at least 95% (w/w) erosion of the        erodible insert, by at least 98% erosion of the erodible insert        or by about 100% (w/w) erosion of the erodible insert.    -   96. The GRDF according to any of clauses 94-95, wherein the GRDF        further comprises a biasing member and at least one hinge        assembly, wherein the biasing member and the at least one hinge        assembly are connected by an elastic element.    -   97. The GRDF according to clause 96, wherein the elastic element        is stretched when the GRDF is maintained in the compressed        configuration.    -   98. The GRDF according to clause 97, wherein the elastic element        maintains its elastic properties with minimal to no plastic        deformation for at least 2 months, at least 4 months, at least        one year or at least 2 years.    -   99. The GRDF according to any of clauses 96-98, wherein the        elastic element comprises, or is made of, silicone rubber.    -   100. The GRDF according to any of clauses 96-99, wherein the        elastic element has a minimal tensile strength of 8.5 GPa and        minimal elongation of 500% as tested in ASTM D412.    -   101. The GRDF according to clause 100, wherein the elastic        element further has hardness of 40-80 shore A as tested in a        D2240 ASTM test.    -   102. The GRDF according to any of clauses 96-101, wherein all        the materials are pharmaceutically acceptable.    -   103. The GRDF according to any of clauses 94-95, wherein the        GRDF is primed for administering to a patient using a mechanism        comprising:        -   a. a body including at least two arms, the body configured            to transform between a collapsed configuration for            ingestion, an expanded configuration for retention within            the stomach and a disassembled configuration, wherein after            a predetermined time period has elapsed, the GRDF            mechanically disassembles into at least two parts such that            each of the disassembled parts of the GRDF is sized for            exiting the stomach,        -   b. an erodible insert comprising a therapeutic agent, a            diagnostic agent, an electronical device, or a combination            thereof;        -   c. a biasing member having a first portion and a second            portion;        -   d. a retainer configured to house the GRDF for ingestion,            wherein the retainer has a main portion and a closing            portion, wherein the retainer is configured to retain the            GRDF in the collapsed configuration; and        -   e. a priming member extending from an interior side of said            closing portion of the retainer,    -   and further comprising the steps of:        -   i. locating said GRDF in said main portion, wherein the GRDF            is in a collapsed configuration;        -   ii. attaching the closing portion to the main portion of the            retainer;        -   iii. pressing the closing portion in the direction of the            main body so that said priming member pushes said first            portion of the biasing member to a position perpendicular to            said second portion of the priming biasing;        -   thereby priming the GRDF for administering to the patient.    -   104. The GRDF according to clause 103, wherein the GRDF further        comprises a retaining element configured to retain the biasing        member in a primed state until dissolution of the retainer.    -   105. The GRDF according to any of clauses 103-104, wherein the        retainer is a capsule, a wrapper, or band surrounding the GRDF.    -   106. An erodible insert configured to be contained in a GRDF,        wherein the erodible insert comprises a therapeutic agent, a        diagnostic agent, an electronical device, or a combination        thereof, wherein the GRDF comprises said erodible insert and a        body comprising at least two arms, the body configured to        transform between a collapsed configuration for ingestion, an        expanded configuration for retention within the stomach and a        disassembled configuration, wherein after a predetermined time        period has elapsed, the GRDF disassembles into at least two        parts such that each of the disassembled parts of the GRDF is        sized for exiting the stomach, wherein the disassembled        configuration is induced by at least partial erosion of said        erodible insert, wherein at least a portion of at least one arm        of said at least two arms forms a sleeve, tube or shell, wherein        said sleeve, tube or shell comprises a cavity, wherein the        cavity is configured to house the erodible insert, wherein the        erodible insert is contained in the cavity, wherein the erodible        insert is partially coated with a gastric-non-erodible coating.    -   107. The GRDF according to any of clauses 82-83 and 94-95        wherein % release (w/w) or % erosion (w/w) is measured using        simulated gastric conditions in a rotating bottle apparatus at        37° C. at 2.5 RPM having 400 mL, pH2 and Xanthan gum 0.125 gr/L.    -   108. A method of delivering a therapeutic agent, a diagnostic,        an electronic device, or combination thereof to the stomach of a        subject for an extended period of time comprising: providing a        GRDF according to any of clauses 1-72, 83-85 or 94-105, wherein        at least one of the arms houses an erodible insert comprising a        therapeutic agent, a diagnostic, an electronic device, or        combination thereof    -   109. A method of delivering a therapeutic agent, a diagnostic,        an electronic device, or combination thereof to the stomach of a        subject for an extended period of time comprising: administering        a GRDF according to any of clauses 1-72, 83-85 or 94-105, to a        patient.    -   110. The GRDF according to any of clauses 7-72 or 83-85 wherein        each of the at least two parts comprises at least one arm and/or        at least one hinge assembly.    -   111. The GRDF according to any of clauses 94-105 wherein the        body further comprise at least one hinge assembly and wherein        each of the at least two parts comprises at least one arm and/or        at least one hinge assembly.    -   112. A gastroretentive dosage form (GRDF) for extended retention        in a human stomach, comprising:        -   c. a body comprising at least two arms, the body configured            to transform between a collapsed configuration for            ingestion, an expanded configuration for retention within            the stomach and a disassembled configuration wherein after a            predetermined time period has elapsed, the GRDF mechanically            disassembles into at least two parts such that each of the            disassembled parts of the GRDF is sized for exiting the            stomach, wherein the body further comprises at least one            hinge assembly and wherein each of said at least two parts            comprises at least one arm and/or at least one hinge            assembly; and        -   d. an erodible insert comprising a therapeutic agent, a            diagnostic agent, an electronical device, or a combination            thereof;        -   wherein the disassembled configuration is induced by at            least partial erosion of the erodible insert, and wherein            the GRDF is adapted to be retained in the stomach for at            least 3 days, at least 4 days, at least 4.7 days, at least 5            days, at least 6 days, at least 6.6 days, at least 7 days,            at least 8 days, or at least 8.3 days.    -   113. A GRDF for extended retention in a human stomach, the GRDF        comprising:        -   a. a body comprising at least two arms, the body configured            to transform between a collapsed configuration for            ingestion, an expanded configuration for retention within            the stomach and a disassembled configuration wherein after a            predetermined time period has elapsed, the GRDF mechanically            disassembles into at least two parts such that each of the            disassembled parts of the GRDF is sized for exiting the            stomach, wherein the body further comprises at least one            hinge assembly and wherein each of said at least two parts            comprises at least one arm and/or at least one hinge            assembly; and        -   b. an erodible insert comprising a therapeutic agent, a            diagnostic agent, an electronical device, or a combination            thereof wherein the erodible insert has two opposing ends;        -   wherein the GRDF further comprises a retainer surrounding            the GRDF and configured to retain the GRDF in the collapsed            configuration; wherein transformation of the GRDF from the            collapsed configuration to the expanded configuration is            induced by erosion of the retainer; wherein at least a            portion of at least one arm of said at least two arms forms            a sleeve, tube or shell, wherein the sleeve, tube or shell            of said at least one arm comprises a cavity, the cavity            housing the erodible insert; wherein said sleeve, tube or            shell of said at least one arm includes at least one opening            configured to allow penetration of gastric fluid into the            cavity, wherein an uncoated surface area on said erodible            insert overlaps with said at least one opening in said            sleeve, tube or shell thereby defining at least one            overlapping area which is exposed to gastric fluid; wherein            erosion of the erodible insert progresses from the at least            one overlapping area towards said two opposing ends of said            erodible insert, and wherein the disassembled configuration            of the GRDF is induced by at least 70% (w/w) erosion of said            erodible insert.    -   114. The GRDF according to clause 113, wherein the disassembled        configuration of the GRDF is induced by at least 80% (w/w)        erosion of the erodible insert, by at least 87% (w/w) erosion of        the erodible insert, by at least 95% (w/w) erosion of the        erodible insert, by at least 98% erosion of the erodible insert        or by about 100% (w/w) erosion of the erodible insert.    -   115. The mechanism for priming or the GRDF according to any of        the previous clauses, wherein the GRDF disassembly into the at        least two parts is a mechanical disassembly.

Definitions

The wording herein below is implied in the common meaning of thedefinitions and statements as known to those skilled in the art.However, there are several terms that should be understood in theconcept of the present disclosure as follows:

As use herein, “gastric-non-erodible” or “gastric non-degradable” or“gastric-fluid-insoluble” coating means a coating which does notdegrade, dissolve or disintegrate in the gastric environment. Suchcoating, when applied onto e.g. parts of a GRDF, obviates or reducestheir dissolution or disintegration in the gastric environment. In anembodiment, the gastric-non-erodible coating is an enteric coating. Inan embodiment, the body of the GRDF of the present invention is at leastpartially coated by a gastric-non-erodible coating. In an embodiment, atleast two arms of the GRDF of the present invention are at leastpartially coated by a gastric-non-erodible coating. In a furtherembodiment, three arms of the GRDF of the present invention and thehinge assemblies are at least partially coated by a gastric-non-erodiblecoating. In a further embodiment, the erodible insert of the presentinvention is at least partially coated by a gastric-non-erodiblecoating. In a further embodiment, at least one tablet out of the tabletsforming the erodible insert of the present invention is at leastpartially coated by a gastric-non-erodible coating. In a furtherembodiment, all the tablets forming the erodible insert of the presentinvention are at least partially coated by a gastric-non-erodiblecoating. The erodible insert may comprise one or more tablets; forexample, 2, 3, 4, 5, 6, 7, 8 or more tablets. The tablets may bearranged side-by-side inside the shell, tube or sleeve in at least onearm of the GRDF. For example there may be two side tablets, each onepositioned at a distal end of the shell, tube or sleeve, and one or morecentral tablets. In an embodiment, only side tablets (e.g. tablets whichare positioned at a distal end of the shell, tube or sleeve, e.g.adjacent to the hinge assembly) are at least partially coated by agastric-non-erodible coating. As used herein, “an uncoated area” of theerodible insert or “an uncoated surface” on the erodible insert or “anuncoated area on the surface of the erodible insert” means an area onthe surface of the erodible insert which is not covered by agastric-non-erodible coating. In an embodiment, at least one uncoatedarea of the erodible insert overlaps, or faces, at least one opening inthe sleeve of an arm housing the erodible insert, thus creating “anoverlapping area/s” which is/are exposed to gastric fluid. In anembodiment, the erodible insert is exclusively exposed to gastric fluidat the overlapping area/s. In an embodiment, the gastric-non-erodiblecoating comprises at least one gastric-non-erodible polymer.

As used herein, “percent release” (% release) of the API or diagnosticagent is the percent amount of the API or diagnostic agent that isreleased into the gastric fluid in the stomach or in simulated gastricconditions (e.g. a rotating bottle apparatus at 37° C. at 2.5 RPM having400 mL, pH2 and Xanthan gum 0.125 gr/L) out of the initial amount of theAPI or diagnostic agent in the composition. The percent release at thetime point of measurement (e.g. at GRDF disassembly) may be calculatedas “% release of the API (weight/w weight=w/w)” which is the percentweight of the API or diagnostic agent that has been released into thefluid, out of the initial weight of the API or diagnostic agent in thecomposition. This may be calculated as follows:

Calculating the weight of the API or diagnostic agent that has beenreleased to the fluid, e.g. in a rotating bottle apparatus at 37° C. at2.5 RPM having 400 mL, pH2 and Xanthan gum 0.125 gr/L (for example bymeasuring the concentration of the API or the diagnostic agent in thefluid, measured e.g. using HPLC, and multiplying by the fluid volume);dividing the calculated released weight by the initial weight of the APIor diagnostic agent in the erodible insert composition; andfurther multiplying the quotient by 100.

As used herein, “percent erosion” (% erosion) of the erodible insert isthe percent amount of the erodible insert composition that is releasedinto the gastric fluid in the stomach or in simulated gastric conditions(e.g. a rotating bottle apparatus at 37° C. at 2.5 RPM having 400 mL,pH2 and Xanthan gum 0.125 gr/L). The percent erosion at the time pointof measurement (e.g. at GRDF disassembly) may be calculated as “%erosion (weight/w weight=w/w)” of the erodible insert, which is thepercent weight of the erodible insert composition that is dissolved intothe gastric fluid in the stomach or in simulated gastric conditions(e.g. a rotating bottle apparatus at 37° C. at 2.5 RPM having 400 mL,pH2 and Xanthan gum 0.125 gr/L) out of the initial weight of theerodible insert composition. This may be calculated as follows:

Subtracting from the initial weight of the erodible insert (includingexcipients and API, diagnostic agent or combination thereof, andexcluding coating if present) the weight of the erodible insert at thetime point of measurement (including excipients and API, diagnosticagent or combination thereof, and excluding coating if present),measured e.g. in a rotating bottle apparatus at 37° C. at 2.5 RPM having400 mL, pH2 and Xanthan gum 0.125 gr/L;dividing the difference by the initial weight of the erodible insert(including excipients and API, diagnostic agent or combination thereof,and excluding coating if present); andfurther multiplying the quotient by 100.

In an embodiment, erosion of the erodible insert is synchronized withthe % release of the API or diagnostic agent (e.g. if the dispersion ofAPI or diagnostic agent in the erodible is generally homogenous).According to this embodiment, % erosion of the erodible insert iscorrelated, similar or preferably very similar to the calculated %release of the API or diagnostic agent.

To note, other ways to evaluate or quantify the size, shape and/orweight of the erodible insert at the time of measurement include but arenot limited to: barium labelling identified using X-ray, scintigraphy,weight loss after drying, and visual observation.

As used herein, an “erodible insert” is any formulation, composition,e.g. in the form of a tablet, tablets or extrudate, which is containedin the body of the GRDF, and which is capable of degradation,dissolution, and/or disintegration based on exposure to gastricenvironment or simulated methods thereof. In an embodiment, an “erodibleinsert” is located inside the sleeve, tube or shell of an arm of theGRDF, e.g. in a cavity inside the sleeve, tube or shell of an arm of theGRDF. In an embodiment, the erodible insert comprises a therapeuticagent, a diagnostic agent, an electronical device, or a combinationthereof. In an embodiment, API dispersion in the erodible insert is nothomogenous. In a preferred embodiment, the API is homogenously dispersedin the formulation forming the erodible insert. Preferably, only aportion of the erodible insert is exposed to the gastric environment. Inan embodiment, the erodible insert is partially coated by agastric-non-erodible coating. To clarify, the dissolution profile of the“erodible insert”, e.g. in the form of a tablet, tablets or extrudate,may be evaluated outside of the human or animal body, e.g. by simulatedmethods (e.g. simulated gastric conditions, e.g. a rotating bottleapparatus at 37° C. at 2.5 RPM having 400 mL, pH2 and Xanthan gum 0.125gr/L). In an embodiment, the erodible insert comprises at least 1, atleast 2, at least 3, at least 4 or at least 5 tablets. In an embodiment,the erodible insert consists of 1, 2, 3, 4 or 5 tablets. In anembodiment, the erodible insert consists of 4 tablets. In an embodiment,the erodible insert consists of 5 tablets. In an embodiment, at leastone tablet comprises a therapeutic agent. In an embodiment, each tabletcomprises a therapeutic agent. In an embodiment, at least one tabletcomprises more than one therapeutic agent. In an embodiment, at leastone tablet is at least partially coated with a gastric-non-erodiblecoating. In an embodiment, each tablet is at least partially coated witha gastric-non-erodible coating. In an embodiment, the erodible insertcomprises more than one therapeutic agent. In an embodiment, theerodible insert is not fastened to the body of the GRDF by a physicalmeasure selected from gluing or tethering. In an embodiment, theerodible insert is not fastened to the at least two arms by a physicalmeasure selected from gluing or tethering.

As used herein, a “gastric-erodible”, “gastric-degradable” or“gastric-fluid-soluble” material, e.g. polymer includes any materiale.g. polymer that degrades, dissolves or disintegrates in the gastricenvironment. As used herein, a “gastric-non-erodible”,“gastric-non-degradable” or “gastric-fluid-insoluble” material, e.g.polymer, includes any material, e.g. polymer that does not degrade,dissolve or disintegrate in the gastric environment.

“Gastric retention”, extended gastric retention”, or “extended retentionin the stomach” (e.g. in the human stomach), as used herein is themaintenance or holding of an agent, for example at least one therapeuticagent, diagnostic agent, electronic device or combination thereof in thestomach for a time period longer than the time it would have beenretained in the stomach when delivered in a free form or within adelivery vehicle which is not considered gastro-retentive. Gastricretentivity may be characterized by retention in the stomach for aperiod that is longer than the normal emptying time from the stomach,such as longer than about 24 hours, 48, 72, 96, 120, 144, 168 hr orlonger. In an embodiment, “gastric retention” or “extended retention” inthe stomach refers to retention in the stomach of a subject for a periodthat is at least 3 days, at least 4 days, at least 4.7 days, at least 5days, at least 6 days, at least 6.6 days, at least 7 days, at least 8days, or at least 8.3 days or longer.

“Gastroretentive dosage form(s)” (GRDF or GRDFs in the plural) refers todosage forms which reside in the confines of a stomach of a subject forthe purpose of providing a platform for the gastric retention oftherapeutic agents, diagnostic agents and/or electronic devices in thestomach. In an embodiment, the GRDF of the present invention is capableof gastric retention. In an embodiment, the GRDF of the presentinvention includes at least a body and an erodible insert comprising atleast one therapeutic agent, diagnostic agent, electronic device orcombination thereof. In an embodiment, the GRDF of the present inventionconsists of a body and an erodible insert comprising at least onetherapeutic agent, diagnostic agent, electronic device or combinationthereof. In a preferred embodiment, at least one therapeutic agent,diagnostic agent, electronic device or combination thereof are containedin an erodible insert present in at least one arm of the GRDF. In anembodiment, the GRDF of the present invention provides gastric retentionof the at least one therapeutic agent, diagnostic agent, electronicdevice or combination thereof which are comprised in the erodibleinsert.

“Gastric residence system”, “gastroretentive delivery system” or “GRS”as used herein refer to a GRDF.

As used herein, a size “suitable for swallowing” is any size and/orshape that are capable of being safely swallowed by a human. Unlessspecified otherwise, size for retention or reference to anatomy such asstomach or pyloric valve are in reference a human.

As used herein, a “body” is meant to include any collection of parts ormaterials that are more or less constrained or otherwise connected tomove together by translation or rotation. The “body” of the GRDF of thepresent invention includes all parts of the GRDF excluding the erodibleinsert. At the very least, the body of the GRDF disclosed hereincomprises two arms. In an embodiment, the body of the GRDF of thepresent invention comprises at least two arms and at least on hingeassembly. In a preferred embodiment, the body of the GRDF of the presentinvention comprises at least three arms, two hinge assemblies and abiasing member. In a preferred embodiment, the body of the GRDF of thepresent invention comprises materials, e.g. polymers, which arenon-erodible under gastric conditions, including but not limited tocellulose esters such as cellulose acetate and cellulose butyrate. In apreferred embodiment, the body of the GRDF of the present inventionconsists of materials, e.g. polymers, which are non-erodible undergastric conditions, including but not limited to cellulose esters suchas cellulose acetate and cellulose butyrate. In an embodiment, the bodyof the GRDF of the present invention is at least partially covered by agastric-non-erodible coating, e.g. enteric coating, protecting it fromerosion under gastric conditions.

As used herein, “excipient” refers to an ingredient, or mixture ofingredients, that is used in the formulation of the compositions(including but not limited to the insert, the body parts—arm, etc.) ofthe present disclosure to give desirable characteristics to thecomposition or erodible insert. As used herein, the term“pharmaceutically acceptable” refers to those compounds, materials,compositions, compacts, salts, and/or dosage forms which are, within thescope of sound medical judgment, suitable for contact with the tissuesof human beings and animals without excessive toxicity, irritation,allergic response, or other problematic complications over the desiredduration of treatment commensurate with a reasonable benefit/risk ratio.In some embodiments, the term “pharmaceutically acceptable” meansapproved by a regulatory agency of the Federal or a state government,such as the Inactive Ingredient Database of the FDA or listed in theU.S. Pharmacopeia or other generally recognized internationalpharmacopeia for use in animals, and more particularly in humans.Various pharmaceutically acceptable excipients can be used. In someembodiments, the pharmaceutically acceptable excipient can be, but isnot limited to, an alkaline agent, a stabilizer, an adhesion agent, aseparating agent, a coating agent, an exterior phase component, acontrolled-release component, a solvent, a surfactant, a humectant, abuffering agent, a filler, an emollient, or combinations thereof.Excipients in addition to those discussed herein can include excipientslisted in, though not limited to, Remington: The Science and Practice ofPharmacy, 21st ed. (2005). Inclusion of an excipient in a particularclassification herein (e.g., “solvent”) is intended to illustrate ratherthan limit the role of the excipient. A particular excipient can fallwithin multiple classifications.

As used herein, “pharmaceutical”, “active”, “an active pharmaceuticalingredient (API)”, “therapeutic agent” or “active agent” is meant toinclude any agent that is administered to a subject to treat a disease,disorder, or other clinically recognized condition, or for prophylacticpurposes, and has a clinically significant effect on the body of thesubject to treat and/or prevent the disease, disorder, or condition.Active pharmaceutical ingredients (APIs) may include but are not limitedto the following: prochlorperazine edisylate, ferrous sulfate,albuterol, aminocaproic acid, mecamylamine hydrochloride, procainamidehydrochloride, amphetamine sulfate, methamphetamine hydrochloride,benzphetamine hydrochloride, isoproterenol sulfate, bismuth salts,colchicine, phenmetrazine hydrochloride, bethanechol chloride,methacholine chloride, pilocarpine hydrochloride, atropine sulfate,scopolamine bromide, isopropamide iodide, tridihexethyl chloride,phenformin hydrochloride, metformin, methylphenidate hydrochloride,theophylline cholinate, cephalexin hydrochloride, diphenidol, meclizinehydrochloride, prochlorperazine maleate, phenoxybenzamine,thiethylperazine maleate, anisindione, diphenadione erythrityltetranitrate, digoxin, isoflurophate, acetazolamide, nifedipine,methazolamide, bendroflumethiazide, chlorpropamide, glipizide,glyburide, gliclazide, 4-aminopyridine tobutamide, chlorproamide,tolazamide, acetohexamide, troglitazone, orlistat, bupropion,nefazodone, tolazamide, chlormadinone acetate, phenaglycodol,allopurinol, aluminum aspirin, methotrexate, acetyl sulfisoxazole,hydrocortisone, hydrocorticosterone acetate, cortisone acetate,dexamethasone and its derivatives such as betamethasone, triamcinolone,methyltestosterone, 17-β-estradiol, ethinyl estradiol, ethinyl estradiol3-methyl ether, prednisolone, 17-β-hydroxyprogesterone acetate,19-nor-progesterone, norgestrel, norethindrone, norethisterone,norethiederone, progesterone, norgesterone, norethynodrel, terfenadine,fexofenadine, aspirin, acetaminophen, indomethacin, naproxen,fenoprofen, sulindac, indoprofen, nitroglycerin, isosorbide dinitrate,propranolol, timolol, atenolol, alprenolol, cimetidine, clonidine,imipramine, levodopa, carbidopa, selegiline, chlorpromazine, methyldopa,dihydroxyphenylalanine, calcium gluconate, ketoprofen, ibuprofen,cephalexin, erythromycin, haloperidol, zomepirac, ferrous lactate,vincamine, phenoxybenzamine, diltiazem, milrinone, captropril, mandol,quanbenz, hydrochlorothiazide, ranitidine, flurbiprofen, fenbufen,fluprofen, tolmetin, alclofenac, mefenamic, flufenamic, difuninal,nimodipine, nitrendipine, nisoldipine, nicardipine, felodipine,lidoflazine, tiapamil, gallopamil, amlodipine, mioflazine, lisinopril,enalapril, captopril, ramipril, enalaprilat, famotidine, nizatidine,sucralfate, etintidine, tetratolol, minoxidil, chlordiazepoxide,diazepam, amitriptyline, and imipramine, and pharmaceutical salts ofthese active agents. Further examples are proteins and peptides whichinclude, but are not limited to, cyclosporins such as cyclosporine A,insulin, glucagon, thyroid stimulating hormone, parathyroid andpituitary hormones, calcitonin, renin, prolactin, corticotrophin,thyrotropic hormone, follicle stimulating hormone, chorionicgonadotropin, gonadotropin releasing hormone, bovine somatotropin,porcine somatropin, oxytocin, vasopressin, prolactin, somatostatin,lypressin, pancreozymin, luteinizing hormone, LHRH, interferons,interleukins, growth hormones such as human growth hormone, bovinegrowth hormone and porcine growth hormone, fertility inhibitors such asthe prostaglandins, fertility promoters, growth factors, and humanpancreas hormone releasing factor. Listings of additional examples ofknown therapeutic agents can be found, for example, in the United StatesPharmacopeia (USP), Goodman and Gilman's The Pharmacological Basis ofTherapeutics, 10th Ed., McGraw Hill, 2001; Katzung, B. (ed.) Basic andClinical Pharmacology, McGraw-Hill/Appleton & Lange; 8th edition (Sep.21, 2000); Physician's Desk Reference (Thomson Publishing), and/or TheMerck Manual of Diagnosis and Therapy, 17th ed. (1999), or the 18th ed(2006) following its publication, Mark H. Beers and Robert Berkow(eds.), Merck Publishing Group, or, in the case of animals, The MerckVeterinary Manual, 9th ed., Kahn, C A (ed.), Merck Publishing Group,2005; and “Approved Drug Products with Therapeutic Equivalence andEvaluations,” published by the United States Food and DrugAdministration (F.D.A.) (the “Orange Book”). Examples of drugs approvedfor human use are listed by the FDA under 21 C.F.R. §§ 330.5, 331through 361, and 440 through 460, incorporated herein by reference;drugs for veterinary use are listed by the FDA under 21 C.F.R. §§ 500through 589, incorporated herein by reference. In certain embodiments,the therapeutic agent is a small molecule. In certain embodiments, thetherapeutic agent may include one or more therapeutic agents. Theerodible insert may hold two or more therapeutic agents which may bepresented as separate components or may be admixed and presentedtogether in a single form, for example, tablet.

A wide variety of APIs may be employed in accordance with the aspects ofthe present disclosure. Relevant APIs are not limited to, but mayinclude the following: APIs acting locally in the stomach; APIsprimarily absorbed in the stomach; APIs poorly soluble in alkaline pH;APIs with narrow windows of absorption; APIs with poor patientadherence; APIs absorbed rapidly from the GI tract; APIs that degrade inthe colon; and APIs that disturb colonic microbes. In addition,“diagnostics” or “a diagnostic agent” which may be employed inaccordance with the aspects of the present disclosure include but arenot limited to medical imaging systems (e.g. scanner, MRI, camera,gastric stimulator, radiolabeled agents and the like. Electronic deviceswhich may be employed in accordance with the aspects of the presentdisclosure include but are not limited to microchips, imaging systems,transmitters and the like.

As used herein, “gastric retentive endpoint” may be dependent on a “timedependent disassembly mechanism” or “timed disassembly” or “timeddownsizing” wherein the GRDF loses its mechanical integrity by“mechanical disassembly”, through a mechanical event exemplified by:cleaving a connection between a first arm and another arm or pivotalconnection thereof for example a hinge assembly.

As used herein, “mechanical disassembly” or “GRDF disassembly” or“disassembly of the GRDF” refers to the disengagement of the GRDF intoat least two parts, wherein the parts of the body of the GRDF comprisedin each part of the at least two parts substantially retain theiroriginal size, shape and/or weight. Mechanical disassembly may resulte.g. from the erosion of the erodible insert, leading to disengagementof least one hinge assembly hinge assembly from at least one arm. Toclarify, the mechanical disassembly, or GRDF disassembly excludesdisassembly into at least two parts wherein at least one part consistsof the erodible insert. Rather, each of the at least two parts resultingfrom mechanical disassembly includes at least one arm and/or at leastone hinge assembly.

As used herein, “pharmaceutical-releasing” is meant to include anyformulation which is designed to undergo degradation, dissolution,disintegration etc. when exposed to the gastric environment, resultingin release of API. Pharmaceutical formulations can include one or moretherapeutic agents or active pharmaceutical ingredients.

As used herein, the “retainer”, “erodible wrapper” or“gastric-fluid-erodible wrapper” refers to any standard means forpackaging pharmaceuticals for delivery into the stomach, such ascapsules. The means may erode, dissolve and/or disintegrate withinminutes of reaching the gastric environment.

As used herein, the term “arm” or “arms” includes any structure thatincludes a length, width and thickness and aids in achieving a device ofa size suitable for gastric retention. In some embodiments, the lengthof each arm may be about at least 1.5 or at least 2.0 or at least 2.5 orabout 2.5 to about 3.0 or at most 3.0 or at most 2.8 or at most 2.7 orat most 2.6. At least one arm of the GRDF as described herein retains anactive pharmaceutical, diagnostic, electronic device etc. For example,the at least one arm may define a cavity therein configured to retain anerodible insert.

As used herein, the term “hinge assembly” includes any mechanism adaptedto permit relative pivotal movement between two or more structures,e.g., arms. The hinge assembly may be consist of one integral part(e.g., a living hinge) or one or more parts that are assembled in theconventional sense. The hinge assembly may attach to one or more arms inboth the collapsed and expanded configurations. The hinge assembly maybe capable of, at a predetermined time or upon occurrence of amechanical event, disengaging from the one or more arms. In anembodiment of the present disclosure, the hinge assembly disengages fromat least one arm as a result of the erosion of the erodible insert. In apreferred embodiment, the hinge assembly disengages from the at leastone arm as a result of the erosion of the erodible insert, wherein thehinge assembly substantially retains its original size, shape or weight.

As used herein “sealing element” includes any structure which isdesigned to prevent leakage from the gastric environment or simulatedmethods thereof, into the cavity in the arm of the gastric retentivesystem.

As used herein, “sum exposure area” or “sum area of the overlappingareas” or “sum area of the overlapping surfaces” or” or “sum area of theexposed surfaces” means the sum area of the surface/s of the erodibleinsert that is/are exposed to gastric fluid in the stomach or undersimulated gastric conditions. In an embodiment, an exposed surface ofthe erodible insert is the overlapping surface between the opening/s inthe sleeve or tube housing the erodible insert, (illustrated by openingsR1, R2, R3, R4 and R5 in FIGS. 21A and 21B), and the uncoated area ofthe erodible insert. In some embodiments, there is one overlappingsurface. In some embodiments, there are more than one overlappingsurfaces. The sum exposure area may be adjusted by the person skilled inthe art in order to control the retention time in the stomach. In anembodiment, the “sum exposure area” is about 15.5 to about 59.8 mm². Inan embodiment, the “sum exposure area” is less than 59.8 mm², or the sumexposure area is less than 40.7 mm², or the sum exposure area is lessthan 15.5 mm². In an embodiment, the sum exposure area is less than 59.8mm² and the gastric retention time is at least 4.6 days, or the sumexposure area is less than 40.7 mm² and the gastric retention time is atleast 6.6 days, or the sum exposure area is less than 15.5 mm² and thegastric retention time is at least 8.3 days.

As used herein, the terms “compressed configuration” and “collapsedconfiguration” are used interchangeably and refer to a state prior toingestion where the GRDF has a size suitable for swallowing.

As used herein, the term “expanded configuration” is a state afteringestion where the GRDF is in a state that permits retention in thestomach (gastric retention) and prevention of passage through thepyloric valve.

As used herein, the term “upon exposure to gastric fluid” or “undersimulated gastric conditions” or “upon exposure to gastric juice”,unless expressed otherwise is meant to be taken literally or whenneeded, based on a suitable model. One example of such a suitable modelincludes a rotating bottle apparatus at 37° C. at 2-5 RPM having 400 mL0.01N HCl, pH2 and optionally Xanthan gum 0.125 gr/L.

As used herein, the term “pharmaceutically acceptable” refers to amaterial that is not physically or otherwise unacceptable when used inaccordance with the disclosure. For example, the term “pharmaceuticallyacceptable carrier” refers to a material that can be incorporated into acomposition and administered to a patient without causing unacceptablephysiological effects or interacting in an unacceptable manner withother components of the composition. Such pharmaceutically acceptablematerials typically have met the required standards of toxicological andmanufacturing testing, and include those materials identified assuitable inactive ingredients by the U.S. Food and Drug Administration.

As used herein, any term relating to geometric terms, shape and/ororientation shall, unless otherwise defined or indicated, be understoodto indicate conformance to the mathematical definition of such term tothe extent possible for the subject matter so characterized as would beunderstood by one skilled in the art and would not to require absoluteconformance to a mathematical definition of such term. Examples of suchterms relating to geometric terms, shape and/or orientation include, butare not limited to terms descriptive of: shape (such as, round, square,circular/circle, rectangular/rectangle, triangular/triangle,cylindrical/cylinder, elliptical/ellipse, (n)polygonal/(n)polygon,vertex etc.); angular orientation (such as perpendicular, orthogonal,parallel, vertical, horizontal, collinear, etc.); contour and/ortrajectory (such as, plane/planar, coplanar, hemispherical,semi-hemispherical, line/linear, hyperbolic, parabolic, flat, curved,straight, arcuate, sinusoidal, tangent/tangential, etc.); surface and/orbulk material properties, spatial/temporal resolution, distribution(such as, smooth, reflective, transparent, clear, opaque, rigid,impermeable, uniform(ly), inert, non-wettable, insoluble, steady,invariant, constant, homogeneous, etc.); as well as many others thatwould be apparent to those skilled in the relevant art. As one example,a system that would be described herein as being “square” would notrequire such article to have faces or sides that are perfectly planar orlinear and that intersect at angles of exactly 90 degrees (indeed, suchan article can only exist as a mathematical abstraction), but rather,the shape of such article should be interpreted as approximating a“square,” as defined mathematically, to an extent typically achievableand achieved for the recited fabrication technique as would beunderstood by those skilled in the art or as specifically described.

In the following description the terms “house”, “contain”, “received”(for example where the erodible insert is described as being received inthe cavity) are all used synonymously and are used to mean “heldwithin”. The skilled person will appreciate that these terms are usedinterchangeably without any change in scope.

As used herein, the terms “constructed from” “consists of” and “formedof” may be used interchangeably and are intended to mean that acomponent is made from or otherwise comprises a specified material. Theterm “substantially” is intended to mean considerable in extent orlargely but not necessarily wholly that which is specified. For example,substantially comprising a particular material may refer to comprisingat least 60%, 70%, 80%, 90%, 95% or more of that material. As useherein, substantially maintaining weight, means maintaining of at least80%, at least 90% or at least 95% of its original weight, measured e.g.in simulated gastric conditions, e.g. as measured in rotating bottleapparatus at 37° C. at 2.5 RPM having 400 mL, pH2 and Xanthan gum 0.125gr/L.

As used herein, the term “opening force” is intended to describe theforce of bias by the compressed state GRDF to open into the expandedconfiguration as illustrated, for example in F1 of FIGS. 20A and 20B orat least progress by 10% towards the expanded state configuration. Theopening force may be calculated by deriving the minimum force requiredto maintain the gastric retentive device in compressed state as measuredon a rigid surface.

As used herein, the term “rigidity” is the property of a GRDF whichexpresses the ability to resist change in size despite application of aforce. In this case, it is the extent to which the GRDF is capable ofresistance to a 10% decrease in any dimension of the expanded state uponapplication of a minimum force, as illustrated for example in F2 in FIG.20 .

As used herein, “retaining elements” are parts of the GRDF which fastenat least two parts of the GRDF one to each other. In an embodiment, theretaining elements are an integral part of the hinge assembly. In anembodiment, the retaining elements include protrusions extending fromtop and or bottom of the hinge assemblies, fitting into niches withinthe arm housing the erodible insert (the “mediating arm”). In anembodiment, the presence of the erodible insert tablets in the cavitymaintains the protrusions within the niches until a certain extent oferosion and disassembly. In an embodiment, when the erodible insert iseroded to a certain extent, the protrusions are released from the nichesso that the hinge assembly disengages form the mediating arm.

Description of GRDF

The present disclosure provides a GRDF and a method of use thereof. TheGRDF is swallowed in a compressed configuration, expands in the stomach,performs its intended function for an extended time period, and at theend of the time period or upon occurrence of a mechanical event,mechanically disassembles into its separate parts for eventual passagethrough the pyloric valve of the stomach.

After exiting the stomach, the disassembled parts of the GRDF safelypass through the rest of the gastrointestinal system and are expelledfrom the body and/or are gradually eroded by pH conditions of theintestine. In some examples, disassembled parts are configured topartially or completely disintegrate after exiting the stomach. In otherexamples, the disassembled parts are configured to disintegrate to anextent necessary for evacuation from the body. In yet other examples,parts of the GRDF do not disintegrate and are evacuated intact.

According to the example, the GRDF described in detail below has a size,strength and shape that facilitates gastric residence as will bediscussed in further detail below, and is configured to resistdegradation, dissolution, erosion in the stomach until the required timeat which point it is configured to disassemble for safe passage out ofthe stomach into the intestinal environment. The erodible insert locatedin the GRDF is configured to degrade, dissolve, erode or downsize in thestomach thereby controlling the time at which the size and strength ofthe GRDF is lost resulting in disassembly such that passage of the partsof the GRDF from the gastric environment is possible. It will beappreciated that because the erodible insert is for the most partlocated internal to the GRDF (except for a limited surface of erosion),the characteristics of the GRDF are maintained until a period of timeclose to the GRDF disassembly event.

The GRDF has collapsed or compressed, expanded and disassembledconfigurations. FIGS. 1A and 1B show an example of a GRDF in theexpanded configuration. The GRDF of FIG. 1A comprises an articulatedbody that includes three arms 1001, 1002 and 1003. Arms 1001 and 1002are pivotally connected to the ends of arm 1003. In the illustratedexample, arms 1001 and 1002 are pivotally connected to arm 1003 by meansof two hinge assemblies 1021, 1020. Arms 1001 and 1003 extend from, andmay pivot around hinge assembly 1020; arms 1002 and 1003 extend from,and may pivot around hinge assembly 1021. In a preferred example, arm1003 is not pivoted around hinge assemblies 1020 and 1021. Instead, arm1001 is pivoted around hinge assembly 1020 and arm 1002 is pivotedaround hinge assembly 1021.

In the expanded configuration of the GRDF, the arms 1001, 1002, 1003form a closed circuit—e.g. a polygon or circle. It will be appreciatedthat although the term polygon is used throughout, in a case that thesides or arms have a curved shape in expanded state, the final shape mayresemble a circle. In the non-limiting example of FIGS. 1A-1B and 2B thepolygon is a triangle such that the three arms form a generallytriangular shape. It will be appreciated however that polygonscomprising more than three sides are also contemplated. The triangle maybe any form of triangle, for example an isosceles triangle or anequilateral triangle. The triangle has three vertices—1030A-1030C (theterm vertex, which may also be referred to as apex, is a mathematicalterm for each angular point or corner of a polygon). As discussed below,in the example of FIGS. 1-2 , vertices 1030A-1030B are ‘hinged’ whilevertex 1030C is ‘hinge less’ in that arms 1002 and 1001 are notpivotally connected to one another. In the illustrated example vertex1030C is formed in situ as the GRDF transitions from a collapsed to anexpanded state.

Also illustrated in the drawings is elastic leaf spring 1006 whichmechanically biases the GRDF from a collapsed state to an expandedstate. 1006 applies a torque on 1002 around 1021.

In the exemplary GRDFs of FIGS. 1A-1B, arms 1001-1003 thereof form aclosed circuit (e.g. polygon). In the GRDF of FIGS. 1A-1B, arms1001-1003 are effectively sides (e.g. elongated sides) of a closedpolygon when the GRDF is in the expanded configuration. Although arms1001-1003 are straight in their elongate direction in the example ofFIGS. 1-2 , this is not a requirement and one or more of the arms mayalternatively be curved.

Arms 1001, 1002 and 1003 are all formed of a relatively rigid materialsuch that they maintain their shape in both the expanded and compressedconfigurations. Thus the body is provided with sufficient strength towithstand the forces acting on it in both fasted and fed conditions ofthe stomach. In the illustrated example, the length of arms 1001, 1002and 1003 are each individually comparable to the length of therespective arms in the compressed form and the width of each arm iscomparable to the width of the compressed form. The depth of the armswhen arranged in the compressed configuration is comparable to the depthof the respective arms in the compressed form. In the presentdisclosure, length is considered to correspond to the x-axis illustratedin FIG. 1A, width is considered to correspond to the z axis illustratedin FIG. 1A and depth is considered to correspond to the y axisillustrated in FIG. 1A.

In the example of FIGS. 1A-1B, hinge assemblies 1020, 1021 are attachedto each end of arm 1003, thus, arm 1003 may be referred to as a‘mediating’ arm. The mediating arm can be configured to provide a timeddisassembly or alternatively can be configured to contain an active,diagnostic and/or electronic. In some examples where the mediating armprovides a timed disassembly, an active, diagnostic and/or electronicmay form another part of the GRDF. In some examples, the mediating armcan be configured to provide a timed disassembly and to contain anactive, diagnostic and/or electronic.

As will be discussed below, arm 1003 has a cavity in which an insert canbe located.

As shown in FIG. 1B, an opening, 1007, is provided in arm 1003 to permitgastric fluid to enter the cavity when the system is in the stomach.Opening 1007 is illustrative of one or more openings in arm 1003 whichcan be localized at the external as well as the internal face of arm1003.

In the illustrated example, arm 1003 is in the form of a tube or sleeve.In the illustrated example the tube or sleeve has a circular crosssection and is thus in the form of a hollow cylinder having a cavity.However the tube may have alternative cross-sectional shapes such assquare or rectangular. In some examples the cross section of the tube isan irregular polygonal shape. As discussed above, the tube is arrangedto house an erodible insert, 1036, as shown in FIGS. 2A and 2B. In someexamples the erodible insert has a complementing contour to the interiorof the tube. In other examples the erodible insert fills only a portionof the interior of the tube. The tube may in any case be considered toform a shell or sleeve that surrounds an erodible insert, diagnostic orelectronic device or combinations thereof. The tube, shell or sleeve hasmechanical durability independent of its contents throughout itsduration in the stomach.

The tube or sleeve may be constructed from material that is insoluble ingastric fluid. Alternatively the outer surface of the tube or sleevecomprises a pharmaceutically acceptable material which is insoluble ingastric fluid, for example at about 37 degrees C. As will be discussedbelow, in some embodiments, an erodible insert which may be in the formof one or more tablets (e.g. pharmaceutical-containing) may be disposedwithin arm 1003.

Arms 1001 and 1002 have a different construction than arm 1003 to allowthe GRDF to be compressed to a compressed or collapsed configuration.Specifically, in the illustrated example, arms 1001 and 1002 have agenerally hollow semi-cylindrical shape. Put another way, arms 1001 and1002 are hollow and have a generally semi-circular cross section. Theends of arms 1001 and 1002 distal to arm 1003 are in the shape of aquarter hemispheres that closes what would otherwise be an open end ofarms 1001 and 1002. Since arm 1003 has a substantially cylindrical shapeand arms 1001 and 1002 have a generally hollow semi-cylindrical shape,the arms are able to overlay one another for example to form a nestedarrangement in the compressed configuration as illustrated in FIG. 4C.

As discussed above, the shell or sleeve of arm 1003 may define at leastone opening, void or window 1007 therein via which gastric fluid canpenetrate the system so as to erode (e.g. pharmaceutical-containingerodible) the erodible insert disposed within the shell or sleeve. Insome embodiments, this opening or window 1007 is relatively small—aswill be discussed below, allowing for a controlled and/or directionalerosion of the erodible insert. In the non-limiting illustrated example,a single opening or window is shown—it is appreciated that in otherembodiments, a plurality of openings or windows may be provided.

The erodible insert may comprise a therapeutic agent, a diagnosticagent, an electronic device or combination thereof. For example, wherethe erodible insert is a therapeutic-agent-containing erodible insert,erosion thereof releases the therapeutic-agent into the gastric fluid.Thus, in this case erosion of the erodible insert ispharmaceutical-releasing erosion. FIG. 2A-2B illustrate the erodibleinsert 1036 (e.g. a tablet) within arm 1003. FIG. 2A is a cross sectionof arm 1003 and shows an annular shell 1080 or sleeve that isconstructed of gastric-fluid-insoluble, pharmaceutically acceptablematerial and/or has an outer surface that is gastric-fluid-insoluble.Put another way, annular shell 1080 or sleeve is a protective shell orsleeve so that gastric fluid can preferably enter the cavity only viaopening(s) 1007 (see FIG. 1B), allowing control of the erosion processsuch that for example the erosion is directional for example erodingfrom the centre outwards. In some examples, it may also be appreciatedthat the surface area and rate of erosion remains substantiallyconsistent throughout the erosion process.

In the example of FIGS. 1A-1B, a proximal end of arm 1002 is labelled as1025; a distal end hereof is labelled as 1026; a proximal end of arm1001 is labelled as 1027; a distal end hereof is labelled as 1028.

In the example of FIGS. 1A-1B, pressure applied by leaf spring 1006applied upon arm 1002 provides a torque around hinge assembly 1021. Theleaf spring 1006 is an elastic leaf spring and biases the GRDF into theexpanded configuration, thus the leaf spring 1006 acts as a biasingmember and may be referred to herein as such. In the illustratedexample, the leaf spring 1006 extends between hinge assembly 1020 andarm 1002 in the expanded configuration. However the leaf spring mayextend between arm 1003 and arm 1002 in the expanded configuration. Thebiasing member may extend from or attach to another part of the GRDF.For example, the biasing member may be a portion of the hinge assemblymediating arm. In another example, the biasing member is a separatecomponent.

In order to bias both arms 1001 and 1002 into the expandedconfiguration, the leaf spring is arranged between arm 1003 and arm 1002when the arms overlay one another in the compressed configuration. Inthis manner the leaf spring acts on the arm 1002 which itself acts onthe uppermost arm 1001 thereby biasing both arms into the expandedconfiguration.

As will be discussed below, in some embodiments at least one vertex1030C may be hinge less. In the example of FIGS. 1A-1B (schematicallyillustrated in FIGS. 3A-3B), pressure applied by leaf spring 1006 uponarm 1002 (which provides a torque around hinge assembly 1021) urges asurface of arm 1002 at distal end 1026 thereof against a portion of side1001 at distal end 1028 thereof to provide compression or a compressiveforce there between (see FIG. 3C). This compressive force causes thearms 1001 and 1002 to mechanically engage, thereby locking arms 1001 and1002 together. As illustrated in examples, sustaining of thiscompressive force is required to maintain (e g stably maintain) vertex1030C. As will be discussed below (e.g. in the context ofdisassembly—see FIG. 7 ), in some embodiments, ceasing of thiscompressive force (e.g. due to the ceasing of the torque around hinge1021) dismantles vertex 1030C. Thus, the dismantling of the first vertextriggers a dismantling of a second of the vertices, therebydisassembling the closed polygon into a plurality of parts/units, eachunit being sized for exit from the stomach via the pyloric valve.

FIG. 3A corresponds to FIGS. 1B and 1 s a schematic drawing of thetriangle. In FIG. 3A, a protrusion 1090 of arm 1001 is additionallyillustrated. Arm 1002 acts against the protrusion 1090 when the GRDF isbiased into the expanded configuration. This facilitates retention ofthe GRDF in the expanded configuration. This will be discussed infurther detail below.

Transition of the GRDF of FIGS. 1-3 from the compressed to the expandedstate is now discussed with reference to FIGS. 4-5 . FIG. 4Aschematically illustrates the GRDF of FIG. 1-3 in a compressed state.

FIG. 4B illustrates the collapsed or compressed-state schematically, ina manner similar to that of FIGS. 3A-3B which illustrates the expandedstate schematically.

To better illustrate the various elements of FIG. 4B, FIG. 4Cillustrates the same compressed state of FIGS. 4A-4B in a verticallydistorted view where vertical space is ‘stretched.’

Thus, as shown in FIG. 4B, when in the compressed state, vertex 1030Cdoes not exist. As will be discussed below, vertex 1030C may be formedin situ (e.g. within the stomach) by pressure applied by leaf spring1006 upon side 1002 (i.e. this pressure provides the torque around hingeassembly 1021).

For example, due to the presence of leaf spring 1006, the GRDF ismechanically biased towards an expanded state. Before ingestion, thispressure may be counteracted by an erodible wrapper around the GRDF(e.g. of FIG. 4A). This wrapper or retainer can sustain the GRDF in thecompressed configuration of FIG. 4A-4C. However, when in the stomach,erosion of this wrapper or retainer reduces or eliminates thiscounteracting force, causing the GRDF to transition from the compressedconfiguration to the expanded configuration as shown in FIG. 5 .

The transition from the compressed configuration to the expandedconfiguration may be driven by elastic restoring forces—in the exampleof FIGS. 1-5 the restoring forces of leaf spring 1006. The transitionmay close a circuit (e.g. a polygon) and/or form a vertex (e.g. hingeless vertex) 1030C.

FIGS. 1-5 illustrate various elements of the system that may, indifferent embodiments, be useful for forming and/or sustaining vertex1030C.

FIG. 6 is a flowchart of an extended-release method using anypresently-described gastric retention system.

FIG. 7 illustrates the expanded state of the GRDF and progressiveerosion of the erodible insert in accordance with some embodiments. Inparticular, in some embodiments an erodible insert (e.g. tablet 1036) ispresent in mediating arm 1003—e.g. within a shell or sleeve having atleast one window or opening 1007 via which gastric fluid may penetrate.In accordance with some embodiments, the erodible insert is in directcontact with an inner surface of mediating arm 1003. When an erodibleinsert is present in mediating arm 1003 the combination of the GRDF bodyand erodible insert is referred to as a GRDF.

At time t1 gastric fluid has yet to penetrate into an interior of arm1003 where erodible insert 1036 is disposed. As noted above, in theexample of FIGS. 1-5 , an interior of arm 1003 is mostly sealed from theexternal environment (e.g. gastric fluid). In some examples, the windowor opening 1007 is in a central portion of side/arm 1003. As such, andas illustrated in FIGS. 7 and 8 , over time (e.g. at times t2, t3, t4)erosion of the erodible insert 1036 within arm 1003 is ‘outward’erosion, e.g. from a central point in the arm in both directions towardsarms 1002 and 1001 and hinge assemblies.

In some embodiments, erodible insert 1036 comprises apharmaceutical—thus, the erosion illustrated in FIG. 7 ispharmaceutical-releasing erosion. Although erodible insert 1036 maycomprise a pharmaceutical, any constitution may be envisioned whetheruniform or in layers.

In the illustrated example, the presence of an erodible insert 1036whether a unit (e.g. tablet) or series of inter-fitting units asillustrated in FIG. 11 and FIG. 19D as 2036S and 2036L may maintain anattachment between hinge assembly 1020 or portion thereof and/or hingeassembly 1021 or portion thereof and arm 1003. In this example, erosionof the erodible insert sufficiently modifies geometric and/or mechanicalproperties of insert 1036 (e.g. which is erodible) to detach a hingeassembly 1020 and/or hinge assembly 1021 from arm 1003. The modifiedgeometric and/or mechanical properties of the erodible insert whichresult in detachment of a hinge assembly occur within an inner cavity ofarm 1003. In this manner, the properties of the GRDF remainsubstantially unaltered until mechanical disassembly.

As illustrated in FIG. 9 , this detaching drives opening of the closedcircuit or closed polygon and/or disassembly of the GRDF into units thatare sized for exiting the stomach via the pyloric valve. FIGS. 9B and 9Cillustrate two alternatives for disassembly, wherein 1006 is integrallyconnected to arm 1003 (FIG. 9B) or to hinge assembly 1020 (FIG. 9C).

Further details of a specific example of a GRDF of the presentdisclosure are described in detail below with respect to FIGS. 10-21 .

FIG. 10 illustrates a front view of a GRDF in an expanded configurationwhile FIGS. 19C and 19D illustrate a side view of a sleeve of the GRDFshown in FIG. 10 . The arrangement of this GRDF is similar to thatillustrated in FIG. 1 .

The GRDF illustrated in FIG. 10 includes three arms 2001, 2002 and 2003in a similar manner to that illustrated in FIG. 1 . The three arms 2001,2002 and 2003 together form a body. The body is in the form of agenerally triangular shape with arm 2003 as the base of the triangularshape and arms 2001 and 2002 as the sides of the triangular shape. Arms2001 and 2002 are pivotally connected to the ends of arm 2003 therebyforming two apexes or vertices of the triangular shape. Arms 2001 and2002 are mechanically engaged with one another to form the third apex orvertex of the triangular shape. The triangular shape may be any form oftriangle, for example an isosceles triangle or an equilateral triangle.Due to the triangular arrangement of arms 2001, 2002 and 2003, the angleα or angle β between arms 2001 and 2003, and 2002 and 2003 can each bebetween about 30 degrees and 90 degrees and in some examples is around60 degrees. For example, angle α and angle β may be about 60 degrees.

Although in the illustrated example a triangular shaped expandedconfiguration is illustrated, other shaped expanded configurations arealso envisaged for example, circular (i.e. where arms have curvature),rectangular, rhombus or other quadrilateral shape, hexagonal, octagonaletc. Any suitable polygonal or circular shape may be used.

A biasing member in the form of a leaf spring mechanically biases arm2002 thereby biasing the three arms 2001, 2002 and 2003 into theexpanded configuration. This will be discussed in further detail below.Although in the illustrated example an elongate leaf spring 2006 is usedas a biasing member, other suitable biasing arrangements may also beused. For example, a biasing member in the form of a helical spring andan elongate member may be used. Additional support for the biasingmember may also be included such as an additional biasing member in theform of an elongate leaf spring 2006 a to bias the elongate leaf spring2006 and the 2001 arm. Alternatively the 2006 r ramp which is configuredto bias the elongate leaf spring 2006 from the first arm 2003 mayprovide additional support in transition.

In the illustrated example, arm 2003 is in the form of a tube (See FIG.19C). In this manner the interior of arm 2003 forms a cavity in which anerodible insert (See FIG. 19D) may be located. As can be viewed in FIGS.10, 11, 14B, 15, 16 and 19 , hinge assemblies or sealing elements 2020and 2021 are provided at the open ends of arm, sleeve or tube 2003. Inthe illustrated example, hinge assemblies 2020 and 2021 include hingeassemblies by which arm 2003 is pivotally connected to arms 2001 and2002 respectively. One end of biasing member 2006 is attached to hingeassembly 2020. In the illustrated example the biasing member 2006 isintegrally formed with hinge assembly 2020. In other examples, thebiasing member 2006 may be separately formed and connected to hingeassembly 2020. In yet further examples, the biasing member 2006 may beattached to arm 2003 instead of hinge assembly 2020.

Since arm 2003 contains an erodible insert it may be considered a“mediating arm”, “containing arm” or “loaded arm”. In the illustratedexample only one arm of the GRDF is loaded with an erodible insert.

In the illustrated example, arms 2001 and 2002 are in the form of hollowhalf cylinders (See FIGS. 19A and 19B). Put another way, arms 2001 and2002 are in the form of cylinders that have been cut in half along theirlength. Arms 2001 and 2002 have a similar cross section to arm 2003 soas to correspond to arm 2003. In this manner, the three arms 2001, 2002and 2003 can overlay one another when the system is compressed as willbe discussed in further detail below. Arms 2001 and 2002 are hollow andtherefore do not contain any erodible insert. The arms 2001 and 2002provide structural support in order to provide the body with therequired shape and structure in the expanded configuration. They maytherefore be considered to be structural arms.

FIG. 11 is a cross-sectional view of the GRDF of FIG. 10 and illustratesfurther details of the system. In the cross sectional view of FIG. 11 acavity formed within arm 2003 can be seen more clearly. Opening 2007 isprovided centrally at the base of arm 2003 in the illustrated example toprovide access to the cavity from the exterior of arm 2003. The opening2007 is representative of one or more openings and those may be providedat any suitable location, can be provided on an upper or side surface ofarm 2003 and may be arranged at any point along the length or arm 2003.In the illustrated example only one opening is provided. However inother examples such as presented in FIG. 21A, FIG. 1B and FIG. 22 aplurality of openings may be provided to facilitate ingress of gastricfluid to the GRDF.

Hinge assemblies 2020 and 2021 include retaining elements 20200 and20210, respectively that extend into the interior or cavity of arm 2003.In the illustrated example each hinge assembly 2020 and 2021 includestwo retaining elements 20200 and 20210, respectively. One retainingelement extends from the top of each hinge assembly 2020 and 2021 andone retaining element extends from the bottom of each hinge assembly2020 and 2021 such that when the hinge assemblies 2020 and 2021 arelocated in arm 2003, the retaining elements 20200 and 20210 act on upperand lower surfaces of the interior of arm 2003. However the presentdisclosure is not limited to this arrangement and the retaining elementscan be arranged to extend into arm 2003 at the sides or at any suitablelocation around the interior of arm 2003. Additionally in theillustrated example, two retaining elements are shown, however in otherexamples only one or alternatively more than two retaining elements canbe provided. Any suitable number of retaining elements can be provided.The greater the number of retaining elements the more securely hingeassemblies 2020 and 2021 are held inside arm 2003 for extended periodsof time under gastric conditions.

Retaining elements 20210 and 20200 include protrusions 20210 a and 20200a, respectively, extending radially outward therefrom. The protrusions20210 a and 20200 a are arranged to cooperate with correspondingrecesses in the inner surface of arm 2003. Protrusions 20210 a and 20200a include a shoulder against which an inner surface of the arm 2003abuts. In this manner the retaining elements 20210 and 20200 prevent thehinge assemblies from falling out or being easily removed from arm 2003and assist in retaining the hinge assemblies 2020 and 2021 in arm 2003.It can be appreciated that the contour of the protrusions 20210 a and20200 a, shoulder and arm 2003 may be adjusted to increase thecooperation with the corresponding recesses protrusions as well as thesensitivity to the presence of the insert tablet such that once theinsert erodes to a specific degree, the protrusions 20210 a and 20200 ano longer cooperate with the corresponding recesses in the inner surfaceof the arm 2003.

With reference to FIG. 11 , biasing member 2006 extends from a first endat, or proximal to, hinge assembly 2020, to a distal end at arm 2002.The distal end of biasing member 2006 engages with a protrusion on aninner surface of arm 2002. In the illustrated example three protrusionsare provided adjacent to each other to provide three different locationsfor the biasing member to engage. In alternative examples arm 2002 isprovided with only a single protrusion. In other alternative examplesone or more recesses may be provided in which the biasing member can belocated. By providing either a protrusion or recess against which thebiasing member can locate, the biasing member 2006 can assist inretaining the GRDF in the expanded configuration. However this may notprovide the only means by which the GRDF is retained in the expandedstate. As such, in some examples, the biasing member 2006 does notengage with arm 2002 but simply abuts against it.

FIG. 11 further illustrates the engagement of arms 2001 and 2002 to formthe third apex or vertex of the triangular shape of the system. As canbe seen, an outer surface of arm 2002 engages with an inner or retainingsurface of arm 2001. The force of the biasing member outwards, causesarm 2002 to be pushed against the interior of arm 2001. The outer end ofarm 2001 encloses the outer end of arm 2002 thereby forming an apex orvertex. In this manner arms 2001 and 2002 are locked together therebyretaining the GRDF in the expanded state. The mechanical engagement ofthe ends of arms 2001 and 2002 provides the main force for retaining theGRDF in the expanded state and can therefore be seen as a locking orretention mechanism. Put another way, the free ends of arms 2001 and2003 in the compressed configuration come into contact to provide aclosed circuit in the expanded-state articulated body via a lockingmechanism.

Further details of the locking or retention mechanism are illustrated inFIG. 12 . FIG. 12 illustrates the engagement of arms 2001 and 2002 whenlocked together. As illustrated, arm 2001 includes a tooth 2001 a thatprotrudes therefrom. The tooth 2001 a is tapered or in the form of aramp although other shapes and configurations are also contemplated. Arm2002 has a cut away portion or indentation 2002 a formed on an outersurface thereof at the end of arm 2002 distal to arm 2003. The cut awayportion 2002 a and tooth 2001 a cooperate with one another and provide afurther means of mechanical engagement of arms 2001 and 2002 in additionto the mechanical engagement of the outer surface of arm 2002 with theinner surface of arm 2001 thereby providing additional retaining means,for example against a tangential force that may otherwise result indetachment. In some examples the tooth 2001 a is not present and an edgeor outer surface of arm 2001 cooperates with indentation 2002 a. Inother examples neither the indentation 2002 a nor tooth 2001 a areprovided and the mechanical engagement of the ends of arms 2001 and 2002provides sufficient force to retain the arms in the expanded statetriangular shape.

A plane 2001 c contacts plane 2002 c when a radial force F1 is appliedexternally. Both planes 2001 c and 2002 c are angled such that thecontact between the plane 2001 c and the plane 2002 c keeps arm 2001locked with arm 2002.

In providing a means by which arms 2001 and 2002 are locked together inthe expanded state, the GRDF is provided with sufficient strength toenable it to be retained in the stomach and resist the forces applied bythe stomach under both fed and fasted conditions. The mechanicalstrength afforded by the shape, interaction and engagement of arms 2001,2002 and 2003 in the expanded configuration is sufficient to enable thepreservation of the expanded configuration under gastric conditions.This assists in the provision of gastric retention since the expandedstate of the GRDF is sized so as to be too large to pass through thepyloric valve as will be discussed in further detail below.

FIG. 13 illustrates further features of arms 2001 and 2002. In theillustrated example, an indentation 2002 a in arm 2002 engages with arail or slider 2001 b provided on arm 2001 as the GRDF transitions intothe expanded configuration. Rail 2001 b is in the form of an elongateprotrusion extending from arm 2001. Rail 2001 b extends along the lengthof arm 2001 and is arranged to guide arm 2002 along arm 2001 into thelocked configuration. This rail 2001 b can be considered a guidingmember. The provision of a guiding member keeps arm 2002 in the sameplane as arm 2001 thereby facilitating the compression of the GRDF intoa compressed configuration or the expansion of the GRDF into theexpanded configuration.

FIGS. 14A and 14B illustrate the GRDF in the compressed configuration.FIG. 14A is a front view of the GRDF in the compressed configuration andFIG. 14B is a cross-sectional view of the GRDF in the compressedconfiguration. As illustrated, arms 2001 and 2002 have been pivotedaround to overlay arm 2003. The interior of arm 2002 has a correspondingshape to the exterior of arm 2003 and the interior of arm 2001 has acorresponding shape to the exterior of arm 2002. In the compressedposition, arm 2002 overlays arm 2003 and arm 2001 overlays arm 2002. Inthis manner in the compressed state the arms 2001, 2002 and 2003 areprovided one inside the other or nested together. This provides acompact arrangement that is easy for a patient to ingest for examplewhen contained in a capsule or container.

As discussed above the GRDF of the present disclosure is designed to beswallowed in a compressed configuration, expanded in the stomach,perform its intended function for an extended and predetermined timeperiod, and at the end of the time period or upon occurrence of amechanical event, disassemble and/or disintegrate or preferablydisassemble for eventual passage through the pyloric valve of thestomach. Thus, it is important that the GRDF can withstand the forcesapplied by the stomach and retain its shape and configuration in theexpanded configuration so as to prevent unintentional disassembly intosmaller parts that would fit through the pyloric valve before expiry ofthe predetermined time period and/or before the GRDF has finishedperforming its intended function. The GRDF of the present disclosure isadvantageously able to endure the significant forces applied to it undergastric conditions due to the particular size, shape and strength of theexpanded state thereby enabling the GRDF to perform its intendedfunction for the required period of time. The GRDF is further designedto disassemble into components or parts small enough to pass through thepyloric valve once it has performed its function as will be discussed infurther detail below.

The erodible insert is designed to degrade, erode or change its physicalcharacteristics in the physiological conditions of the gastricenvironment. In an aspect, the erodible insert is the only componentthat degrades, erodes or changes its physical characteristics thephysiological conditions of the gastric environment. Thus erosion of theerodible insert does not cause degradation or erosion of arm 2003, andthe mechanical strength of arm 2003 is maintained throughout erosion ofthe erodible insert. In some examples, the erodible insert can beconfigured to provide directional erosion for example from the center ofthe first arm towards the ends/hinge assemblies. Thus, the erodibleinsert can provide a timed disconnection of the second and/or third armwhich commences at greater than 60% erosion, at greater than 70%erosion, at greater than 80% erosion, at greater than 90% erosion or atgreater than 95% erosion of the erodible insert.

In the example illustrated in FIG. 15A the erodible insert fills theentirety of the cavity in arm 2003. In particular the erodible insert issized such that hinge assemblies 2021 and 2020 have an interference fitbetween the erodible insert and the interior surface of arm 2003. Theclose fit of these components is such that the erodible insert providesan outward or compressive force which pushes resilient protrusions 20210a and 20200 a into the recesses on the interior surface of arm 2003.This ensures that the hinge assemblies 2020 and 2021 remain located inthe ends of arm 2003. In the illustrated example the erodible insert isin the form of one or more tablets.

Once the erodible insert has been inserted into the body thereby forminga GRDF, the system is compressed into the compressed state beforeingestion. The system may be compressed by hand or using a machine ordevice similar to that described in WO2017/093976. After compression thesystem is retained in the compressed state by locating the system insidea capsule or container. The capsule has the additional function ofpreventing gastric fluid from entering opening or openings 2007. Thecapsule is formed of material that is strong enough to withstand theinherent biasing force of the biasing member and thus retains the systemin the compressed state. The capsule material also erodes or dissolvesupon exposure to gastric fluid. Thus once the capsule is ingested by apatient, the capsule erodes in the presence of gastric fluid in thestomach. This removes the force retaining the system i.e. the GRDFcontaining the erodible insert in the compressed configuration. Theinherent bias of the biasing member then biases the GRDF, and thus theoverall system, into the expanded state where it is retained by means ofthe mechanical engagement of arms 2001 and 2002. Thus automatictransformation into the expanded configuration is achieved. Thetransformation of the system into the expanded configuration isindependent of the erodible insert and therefore is solely dependent onthe mechanical arrangement of the GRDF. The GRDF is designed such thatthe transformation from the compressed configuration to the expandedconfiguration occurs rapidly. In some examples the GRDF is configured totransform between the compressed configuration for ingestion and theexpanded configuration for gastric retention within less than 10minutes, less than 5 minutes, less than 4 minutes, less than 3 minutesor preferably less than 2 minutes.

Once the GRDF has been ingested and travels to the stomach, the capsulehas eroded and the GRDF has transformed into the expanded state, theGRDF remains in the stomach for a predetermined period of time. The GRDFis thus sized so that in the expanded state, it cannot exit the stomachthrough the pyloric valve. In order to prevent passage through thepyloric valve, the GRDF in the expanded state must have a minimumturning radius capable of resisting passage through the pyloric valve.“Turning radius” is understood to mean a critical dimension via whichthe system could be rotated and/or turned to fit through an opening, forexample the pyloric valve, ring or a tube having a defined diameter andheight. This is not necessarily the smallest dimension or diameter ofthe GRDF but rather is a function of the 3D geometry of the GRDF (depth,width, length of the GRDF), the dimensions (for example radius r andheight 30 mm) of the valve or simulated model thereof, and amount ofspace on either size of the valve. By providing a GRDF of appropriategeometry, a GRDF that can remain in the stomach for a desired period oftime is provided. For example, the minimum turning radius may bemeasured through rotation in any orientation in attempt to fit through asimulated model of pyloric valve (for e.g. a ring having a defineddiameter).

In one example of the gastric retentive systems disclosed, there isprovided an expanded state device having a smallest turning radiusgreater than about 20 mm or greater than about 22 mm or greater thanabout 24 mm or greater than about 25 mm or greater than about 26 mm. Inanother embodiment, gastric retention may be achieved with a devicehaving smallest turning radius less than 35 mm or less than 32 mm orless than 30 mm or less than 28 mm. In other embodiments, gastricretention may be achieved with a device in expanded state, havingsmallest turning radius between 20 and 35 mm or about 20 mm to about 32mm or between 20 and 30 mm or about 20 to about 28 mm or about 22 and 35mm or about 22 mm to about 32 mm or between 22 and 30 mm or about 22 toabout 28 mm or about 24 and 35 mm or about 24 mm to about 32 mm orbetween 24 and 30 mm or about 24 to about 28 mm or about 24 and 35 mm orabout 24 mm to about 32 mm or between 24 and 30 mm or about 24 to about28 mm or about 26 and 35 mm or about 26 mm to about 32 mm or between 26and 30 mm or about 26 to about 28 mm or about 28 and 35 mm or about 28mm to about 32 mm or between 28 and 30 mm Combinations of theabove-referenced ranges are also possible. The turning radius may bemeasured prior to exposure to gastric environment.

Another way of considering an appropriate size of the GRDF is toconsider the ratio between: (i) a minimum enclosing ring of the GRDF inthe expanded state and (ii) a minimum enclosing ring of the GRDF in thecompressed state. In examples of the GRDF disclosed, the ratio is atleast 1.5 or at least 2 or at least 2.5 and/or at most 10 or at most 7.5or at most 5 or at most 4 or at most 3.5 or at most 3.0. Combinations ofthe above-referenced ranges are also possible. Another way ofconsidering an appropriate size of the GRDF disclosed herein is toconsider a ratio between (i) the post-cleavage length of the mediatingsleeve or tube and a (ii) a pre-cleavage and expanded-state diameter ofa minimum-enclosing sphere of the GRDF, is at least 0.05 or at least 0.1or at least 0.2 or at least 0.3 or at least 0.5. Combinations of theabove-referenced ranges are also possible.

Another way of considering an appropriate size of the GRDF is toconsider the convex hull volume. This term is known to those skilled inthe art to refer to a set of surfaces defined by the periphery of athree-dimensional object such that the surfaces define a volume. In thepresent disclosure, appropriate size refers to a GRDF large enough inthe expanded configuration to prevent passage through the pyloric valveyet small enough in the compressed configuration to enable it to beswallowed. In order to meet these requirements it has been establishedthat a convex hull volume of the compressed configuration is about 20 toabout 40% or about 25 to about 35% or about 30% to about 40% of theconvex hull volume of the expanded configuration. In order to meet theserequirements it has been established that a convex hull volume of theexpanded configuration is about 200 to about 400% or about 250 to about350% or about 300% to about 400% of the convex hull volume of thecompressed configuration. By providing a device with a smallest turningradius of about 20 to about 35 mm or about 22 mm to about 28 in anexpanded configuration and/or a convex hull volume in a compressedconfiguration of about 30% of the expanded configuration convex hullvolume, it is ensured that the GRDF can be safely swallowed in itscompressed configuration yet resistant to passage through the pyloricvalve in the expanded configuration.

After a predetermined time in the stomach during which thepharmaceutical or diagnostic is released, the system disassembles into anumber of smaller parts which are small enough to fit through thepyloric valve and pass out into the intestine and thence out of thebody. The mechanism by which the GRDF disassembles will now be discussedwith reference to FIGS. 15A-15D.

FIG. 15A illustrates the system (i.e. the GRDF containing the erodibleinsert) in the expanded state once the capsule retaining it in thecompressed state has been eroded or dissolved. The dissolution of thecapsule removes a cover over opening 2007 and thus allows gastric fluidto enter arm 2003 via opening 2007. The gastric fluid graduallydissolves or erodes the erodible insert 2036 thereby releasing thepharmaceutical or diagnostic. Once the erodible insert has eroded, thecomponents of the GRDF are each individually sized to exit the stomach.

FIG. 15B illustrates the system when the erodible insert 2036 ispartially eroded. As can be seen in FIG. 15B since opening 2007 iscentrally located in arm 2003, the erosion of the erodible insert 2036is directional erosion from the center of the erodible insert 2036outwards to the ends of the erodible insert 2036.

Referring to FIG. 15C, once the erodible insert 2036 has eroded ordissolved substantially, the outward force on the retaining elements20210 and 20200 decreases. After a certain amount of erosion of theerodible insert 2036, the resilience of the retaining elements 20210 and20200 which are biased inwards overcomes the compressive force of theerodible insert 2036 such that the resilient retaining elements 20200and 20210 may retract out of the recesses in the arm 2003 by applicationof an external force. The protrusions 20210 a and 20200 a aredimensioned such that once they are removed from the recesses in the arm2003; the hinge assemblies 2020, 2021 are no longer retained in the arm2003. Hinge assemblies 2020 and 2021 thereby disassemble from arm 2003.

Typically, the erodible insert is substantially eroded when at leastabout 60% of the erodible insert is eroded, or about at least about 70%,or about at least about 80% or about at least about 90% eroded beforethe compressive force of the erodible insert is reduced sufficiently toenable the retaining elements to retract out of the recesses in arm2003. In other examples at least about 70%, at least about 80% or atleast about 90% of the erodible insert must be eroded to enabledisassembly of the system. The degree of erosion may correspond to theamount of pharmaceutical or diagnostic released.

Upon disassembly of hinge assemblies 2020 and 2021 from arm 2003, arms2001 and 2002 also disassemble from another. FIG. 15D illustrates thecomponents of the GRDF after disassembly of the GRDF. Each of theindividual disassembled components may be small enough to pass throughthe pyloric valve into the intestines and thence out of the body. Inalternative examples, the components may be further downsized forexample by further disassembly or erosion so as to provide individualcomponents small enough to pass through the pyloric valve.

FIGS. 16A-16C illustrates an alternative configuration of the GRDFillustrated in FIGS. 10 and 14 in which the biasing member is an angledelongate member. This configuration is similar to the configurationillustrated in FIGS. 10-14 and therefore only the points of differencewill be described.

In the compressed configuration a first portion 2006 a of the biasingmember extends over arm 2003 in a similar manner to the embodimentdescribed with respect to FIGS. 1-15 above. A second portion 2006 b ofthe biasing member is angled with respect to the first portion 2006 a ofthe biasing member and extends into hinge assembly 2020. When the GRDFis compressed into the compressed state, the majority of the GRDF islocated in a main body 2030 b of a capsule thereby retaining the GRDF inthe compressed configuration. As a closing portion 2030 a of the capsuleis inserted over the hinge assembly 2020 into which the second portion2006 b of the biasing member extends, a priming/cocking member 2031extending from an interior of the closing portion 2030 pushes the secondportion 2006 b of the biasing member to a position perpendicular to thefirst portion 2006 a of the biasing member as shown in FIG. 16B, therebypriming/cocking the biasing member. The second portion 2006 b of thebiasing member is retained in position by a tooth 2040. This way ofpriming/cocking of the biasing member is herein called “horizontalpriming”. Such a mechanism, for example, obviates the need of anexternal cocking device.

Upon erosion of the capsule in gastric conditions, the first portion ofthe biasing member 2006 a acts on arm 2002 in a similar manner to theexample described with respect to FIGS. 10 and 11 to force the systeminto the expanded configuration. FIG. 16C illustrates this alternativearrangement in the expanded configuration. Thus an alternativearrangement of the biasing member has been described which facilitatescompression of the GRDF and insertion into a capsule for ingestion.

FIG. 17 illustrates a front view of alternative example of a GRDFaccording to the present disclosure in an expanded configuration. Thisexample is substantially similar to the examples described with respectto FIGS. 1-16 above and therefore only the points of difference will bedescribed. In this example instead of two structural arms, fourstructural arms are provided. Arms 3001 and 3002 are provided on oneside of containing arm 3003 and arms 3001 a and 3002 a are provided onthe other side of containing arm 3003. A second biasing member 3006 a isprovided to bias arms 3001 a and 3002 a into an expanded configuration.Arms 3001 and 3001 a operate in the same manner and have the samefeatures as arm 2001 in the example described with reference to FIGS.10-16 above. Arms 3002 and 3002 a operate in the same manner and havethe same features as arm 2002 in the example described with reference toFIGS. 10-16 above. Thus arms 3001 and 3002 mechanically engage therebylocking arms 3001, 3002 and 3003 into a first triangular configuration.Similarly arms 3001 a and 3002 a mechanically engage thereby lockingarms 3001 a, 3002 a and 3003 into a second triangular configuration.Thus the expanded configuration of this example includes twosubstantially triangular configurations, one either side of arm 3003.

Biasing members 3006 and 3006 a operate in the same manner and have thesame features as biasing member 2006 in the example described withreference to FIGS. 10-16 above. Biasing member 3006 biases arms 3001 and3002 into the expanded configuration, while biasing member 3006 a biasesarms 3001 a and 3002 a into the expanded configuration. Thus, in theexpanded configuration the body has an overall quadrilateral shape thatincludes two generally triangular shaped sections A and B (FIG. 17 ).

When the GRDF is compressed to a compressed configuration, arm 3001overlays arm 3002 which itself overlays arm 3003 in a similar manner toarms 2001, 2002 and 2003 of the example described with respect to FIGS.10-16 above. Similarly arm 3002 a overlays arm 3001 a which itselfoverlays arm 3003. Thus, a compact compressed arrangement may beprovided which facilitates oral administration.

This example thus provides an alternative arrangement of a GRDF havingthe ability to transform between a compact compressed configuration anda strong expanded configuration that has the ability to withstand theharsh environment and gastric forces of the stomach.

In the example illustrated with respect to FIG. 17 , each of arms 3001,3002, 3001 a and 3002 a is straight. However, arms 3001, 3002, 3001 aand 3002 a could alternatively be of another shape, e.g. curved. Inanother alternative example, arms 3001, 3002, 3001 a and 3002 a may beless rigid than those illustrated such that arms 3001, 3002, 3001 a and3002 a may straight in the compressed configuration but slightly curvedin the expanded configuration. In such an example the overall shape inthe expanded configuration may be elliptical or substantially circular.It will be appreciated that a certain amount of rigidity must bemaintained in order to provide a device of sufficient strength to bemaintained in gastric conditions. However a GRDF in which the mechanicalengagement of arms 3001 and 3002; and 3001 a and 3002 a appliessufficient force to the arms to result in curvature of the arms isenvisaged. Thus in the expanded configuration the GRDF may have anyoverall shape provided it has the size and strength to withstand gastricconditions for a required period of time.

Thus examples of a GRDF that can be retained in the stomach anddisassemble after a predetermined time have been described with respectto FIGS. 1-17 . In the above described examples, the length of timetaken for the erodible insert to erode or dissolve acts as a timer forthe disassembly of the system. In this manner the length of time thesystem can be retained in the stomach can be controlled by control ofthe erodible insert. For example, the erodible insert may be extremelyresistant to erosion or dissolution so as to allow the system to beretained in the stomach for a long period of time. Alternatively theerodible insert may be less resistant to erosion or dissolution and thusthe system may only be retained in the stomach for a short period oftime. In some examples the erodible insert is a solid tablet. In someexamples the erodible insert may be in the form of a plurality oftablets. In some examples each tablet may have the same rate oferosion/dissolution. In other examples the tablets nearest the openingmay have a lower rate of erosion/dissolution and the tablets adjacentthe retaining elements may have a higher rate of erosion/dissolution. Insome examples, such as illustrated by tablets 2036S and 2036L in FIG. 22, the tablets may be coated by a “gastric-non-erodible” coating,allowing liquid to penetrate only through predetermined openings in thecoating and/or openings in the shell such as illustrated in FIG. 21A andFIG. 21C.

In some examples, the erodible insert is configured to load relativelyhigh levels of the active substances. For example, the therapeuticagent-containing erodible insert may comprise at least about 15%, atleast about 20%, at least 30%, at least 40%, at least 50%, at least 60wt %, at least about 70 wt % at least about 80 wt %, at least about 90wt %, or at least about 95 wt % of active of the total weight of theerodible insert. In some examples, the erodible insert compositioncomprises excipients in an amount of up to and including about 90 wt %,up to and including about 80 wt %, up to and including about 70 wt %, upto and including about 60 wt %, or up to and including about 50 wt %, upto and including about 40 wt %, up to and including about 30 wt %, up toand including about 20 wt %, up to and including about 10 wt % of thetotal weight of the erodible insert. Any and all closed ranges that haveendpoints within any of the above-referenced ranges are also possible(e.g., between about 20 wt % and about 30 wt %).

In some examples, the erodible insert comprises about 85 wt % of activepharmaceutical ingredient and about 15 wt % of excipient, about 75 wt %of active pharmaceutical ingredient and about 25 wt % of excipient,about 65 wt % of active pharmaceutical ingredient and about 35 wt % ofexcipient, about 55 wt % of active pharmaceutical ingredient and about45 wt % of excipient, about 45 wt % of active pharmaceutical ingredientand about 55 wt % of excipient, about 35 wt % of active pharmaceuticalingredient and about 65 wt % of excipient, about 25 wt % of activepharmaceutical ingredient and about 75 wt % of excipient or about 15 wt% of active pharmaceutical ingredient and about 85 wt % of excipient.

Referring to FIGS. 10, 11, 15 the location of opening 2007 is a factorin determining the rate of erosion. For example, positioning of opening2007 in the center of arm 2003 provides a state where the distancebetween the opening and each end of the erodible insert 2036 is not lessthen half the length of the erodible insert. Thus maximum erosion mustbe carried out before the retaining elements retract enablingdisassembly of the GRDF, thereby providing a maximum time delay beforedisassembly. Alternatively a plurality of openings may be provided atvarious locations on arm 2003, such as illustrated in FIGS. 21A and B,to increase the amount of gastric fluid entering the GRDF and therebyincrease the rate of erosion. Thus the length of time which the systemis retained in the stomach may be partly controlled by the arrangementsand size of openings in arm 2003 as well as the shape and rate oferosion under gastric conditions of the erodible insert 2036. Forexample, as illustrated in FIGS. 21A and B, R1, R2, R3 R4, and R5 holespartly control extent of fluid entering the cavity. The C holes are thelocation for the protrusion of 20200 and 20210 to lock into the arm andshould not provide any significant exposure to gastric fluid orsimulated gastric fluid. In addition, the erodible insert tablets may bepartially coated by a “gastric-non-erodible” coating, allowing liquid topenetrate only through predetermined openings in the coating. Coating ofthe erodible insert tablets and particularly the side tablets, preventsthe premature exposure of the side tablets to the gastric fluid. Thus,an overlap between the opening/s in the shell such as illustrated inFIG. 21A and FIG. 21B and surface area/s on the erodible insert whichlack coating (“uncoated areas” of the erodible insert), define surfaceareas of the erodible insert which are exposed to gastric fluid. The sumarea of the surface areas of the erodible insert which are exposed togastric fluid is herein referred to as “sum exposure area” or “sum areaof the overlapping areas” or “sum area of the overlapping surfaces” or”or “sum area of the exposed surfaces”.

Referring generally to FIGS. 1-22 , it should be understood that anymethod or mechanism that is configured to maintain the collapsedconfiguration of the GRDF prior to swallowing is envisioned. Theexamples described above include a capsule that erodes or dissolves uponcontact with gastric fluid. In another envisioned example, in a casewhere the natural state of the GRDF is the expanded state, there may bea material holding the GRDF closed which dissolves or erodes in thepresence of gastric fluid thereby releasing the GRDF to an expandedconfiguration. In another example, the material may be in the shape ofan erodible band which encompasses the arms to maintain the GRDF in acollapsed configuration until the band erodes allowing expansion of theGRDF. Still another envisioned example includes a glue-like materialthat keeps the two arms together until the glue-like material erodesallowing expansion of the GRDF.

In the illustrated examples above, and without wishing to be bound totheory, the capsule provides both a retention function for retaining theGRDF in a compressed configuration and a barrier function by providing acover over the opening to the cavity thereby preventing gastric fluidentering the cavity. In alternative examples however the barrierfunction and retention functions may be provided by separate components.For example the opening to the cavity could be sealed by a cover and thecompressed configuration could be maintained by an erodible band.Alternatively an erodible cover could be provided over the opening tothe cavity and a capsule provided to retain the system in the compressedconfiguration. In these examples the erosion rate of the cover may bedifferent to the erosion rate of the capsule or band. In such examplesthe GRDF may transform into the expanded configuration and gastric fluidwould enter the cavity after a further time delay. In an alternativeexample, a further delay may be provided by a portion of the erodibleinsert or, where the erodible insert is formed from a number of erodibleunits, some of the erodible units may be positioned to erode first suchthat there is a delay in delivery of the API or diagnostic. Thus theprovision of an additional cover for preventing gastric fluid enteringthe cavity can provide an additional delay in the delivery of the API ordiagnostic and the disassembly of the system.

It should be understood that other methods or mechanisms configured totransition or open the GRDF to the expanded configuration areencompassed by the present disclosure. In the examples described hereina leaf spring springs outwards and extends from the inner area of one orboth of the arms once the expanding configuration is initiated or oncethe mechanical integrity of the collapsed condition has beencompromised, e.g., capsule is dissolved. Alternatively a rigid member incombination with a helical spring could be used instead of the leafspring. In an alternative envisioned example, a superporous hydrogelsystem may be incorporated into the inner part of the arm 2002 whichexpands upon exposure to the gastric environment thereby forcing arm2002 upward against arm 2001 into the expanded configuration. In afurther alternative example, the pivotal connection between arms 2003and 2002 may be formed of an elastic material such that the pivotalconnection itself biases the GRDF into the expanded configuration.

As described in the examples, the mechanical engagement of arms 2001 and2002 (or equally 1001 and 1002 or 3001 and 3002) by arm 2003 (orsimilarly 1003, 3003) locks the arms together into a triangular-shapedstructure with the strength to withstand the forces that will act on itin the stomach and a size to prevent it passing through the pyloricvalve and out of the stomach. In alternative embodiments, additionallocking means may be employed to assist in locking the arms in anexpanded configuration. For example, as described above, an inner facingsurface of arm 2002 may include a locking mechanism to lock the leafspring in place in the expanded configuration. Alternatively the hingeassemblies of the sealing elements or hinge assemblies may include oneor more mechanical interfaces or mechanisms, gear, spring, cam, etc.that are configured to maintain or lock the GRDF in the expandedconfiguration until disassembly. In some examples the leaf spring maysimply be configured to bias the GRDF from the collapsed configurationand not necessarily to maintain the GRDF in the expanded configurationbut may be configured to simply prevent the GRDF from transitioning backto the collapsed configuration.

In the general area of unfolding gastric retentive systems, the force ofopening or measure of mechanical bias towards an expanded state can beassociated with a degree of safety risk in cases where unfolding orexpansion occurs in an undesired location. Undesired locations includefor example, the esophagus midway to stomach; in a crevice in thestomach wall or gastric rugae; or in intestine in cases where thecapsule passes the pyloric valve prior to dissolving. Thus, it is ofparticular interest that in relation to the GRDFs disclosed herein, inone embodiment, the force of opening from the compressed configurationis significantly less than the force to compressing the GRDF from theexpanded configuration. Put another way, the force of the biasing memberacting to transition the GRDF from the compressed configuration into theexpanded configuration is significantly less than the force required tocompress the GRDF by about 10% in any dimension from the expandedconfiguration towards the compressed configuration. For example, theratio of the opening force, applied by the biasing member, to thecompression force, required to compress the GRDF by about 10%, is lessthan about 0.2 or less than about 0.1 or less than about 0.05 or lessthan about 0.03 or less than about 0.02. In examples, the ratio is about0.005 to about 0.2 or 0.005 to about 0.1 or about 0.005 to about 0.05 orabout 0.005 to about 0.03 or about 0.005 to about 0.02. Combinations ofthe above-referenced ranges are also possible. In relation to the GRDFsdisclosed herein, the force to open from the compressed configurationtowards the expanded configuration may be less than about 100 gF, orless than about 50 gF or between about 20 to about 30 gF.

In the examples discussed herein, a cylindrically shaped containing ormediating arm 1003, 2003 or 3003 is described however the containing armmay have any suitable shape that includes a cavity in which an erodibleinsert can be located. In a similar manner, whilst particular shapes ofstructural arms 1001, 2001, 1002 and 2002 have been described, anysuitable shape may be used provided the three arms can form a compressedconfiguration which is small enough to be swallowed. For example thestructural arms may have a solid shape provided the depth of the arms issmall enough to enable the GRDF to compress to a suitable size and shapefor swallowing. In alternative examples, the structural arms may have ahollow shape in the form of an open (i.e. not enclosed) shell in asimilar manner to the specific examples described above. The structuraland containment arms are not limited to any particular cross sectionalshape however in examples where the structural arms are in the form of ashell, the arms are shaped so that an inner surface of structural arms1001/2001 has a corresponding shape to an outer surface of structuralarm 1002/2002; and an inner surface of structural arm 1002/2002 has acorresponding shape to an outer surface of containment arm 1003/2003. Byforming structural arms 1001/2001 and 1002/2002 to have internalsurfaces with corresponding shapes to structural arm 1002/2002 andcontainment arm 1003/2003 respectively, a compact device is providedthat facilitates oral administration of the GRDF.

As noted above, after a pre-determined period of time, the GRDFsdescribed herein will eventually lose their mechanical integrity as asingle unit, disassemble and pass from the stomach for subsequentevacuation. There are many possible mechanisms to achieve this result,all of which are encompassed by the present disclosure. In theillustrated examples above an erodible insert is located in arm 2003,which erodible insert disintegrates or erodes once exposed to gastricfluid thereby causing mechanical disengagement of the hinge assemblies2020 and 2021 from arm 2003 and resulting in a dismantling of at least afirst vertex.

In some embodiments, the GRDFs described herein include an arm having acavity defined therein. The volume of the cavity may range from about100 mm³ to about 800 mm³, about 300 mm³ to about 600 mm³ or about 350mm³ to about 550 mm³. In embodiments, the volume of the cavity is about0.8 ml to about 0.1 ml, or about 0.6 to about 0.3 ml. Depending on thecompressibility of the insert tablet and the cavity design, the volumeof the cavity may provide for an insert tablet comprising a dose of APIin an amount of 700 mg or less, about 250 mg to about 700 mg, or about300 mg to about 600 mg.

In any of the GRDFs described herein, the erodible insert includesexcipients typically used for immediate release or controlled release.However, in a preferred embodiment, controlled release excipients areincluded. The location and amount of exposure of the erodible insert togastric fluid may be controlled through control of the area of theopenings in the arm containing the erodible insert, such as the holespresented in FIG. 21A and FIG. 21B, as well as the location of openingsin the gastric-non-erodible coating of the erodible insert tablets asshown in FIG. 22 , also affecting erosion rate and/or duration.

The materials are selected and processed in a way that will enable eachof the components of the GRDF to operate according to its definedfunctionality (e.g., rigidity for the arms and hinge, elasticity ofspring, and stability in dissolution, as defined above) or desiredmanufacturing method (e.g. hot melt extrusion, injection molding).Different materials may be used in order to better balance betweendurability and safety or eventual disintegration; pH independence anddependence, etc. For example, the ratio of cellulose acetate (CA) totriacetin may contribute to the durability, elasticity, reducedbrittleness, independence from pH changes and decreased erodibility. Inanother example, injection molded pH dependent polymer such as HPMCacetate succinate is at least partially coated with a pH dependentpolymer (e.g., polymethacrylates such as HPMC acetate succinate,Eudragit S®). In another example, molded parts are a combination of pHindependent and pH dependent polymer. Other materials may be selectedfrom PCT/US2015/033850 or PCT/US2016/064439.

In some embodiments, the individual body components such as the arms,hinge, tube or sleeve do not undergo any significant swelling in thepresence of biological fluids such as blood, water, bile, gastricfluids, combinations of these, or the like. For example, in certainembodiments, the individual components swells by less than about 10 vol%, less than about 5 vol %, less than about 2 vol %, or less than about1 vol % in a non-stirred, gastric fluid or simulated gastric fluid atphysiological temperature as compared to the volume of the component inthe dry state (e.g., RT). For example, the molded hinge assembly or armcomponent may comprise enteric polymers (i.e. for example includedduring injection molding) and/or a coat of enteric polymers (i.e. addedpost molding). In another embodiment, digestive track insolublematerials, for example cellulose acetate may be used.

The GRDF of the present disclosure may be manufactured by a number ofprocesses including injection molding, 3D printing and the like, as willbe clear to one skilled in the art, and including the manufacturingtechniques described in WO 2003057197 or in Zema et. al., Journal ofControlled Release, Volume 159 (2012) 324-331. For example, a mold canbe constructed in the desired shape of the components of the GRDF andfilled with appropriate material(s) in liquid state and then allowed tocure by chemical processes or cooled if thermosetting material(s) areused.

The ability to be minimally affected by a repetitive force contributesto the ability of a GR system to maintain a size relevant for gastricretention. In examples of the present disclosure, the GRDFs described indetail above, may include a mechanical durability to remain intact,i.e., assembled with minimum deformation/downsizing when exposed togastric conditions or when a repetitive compressive force is applied,over a period of time of at least about 2 hours, or about 3 hours, orabout 6 hours, or about 9 hours, or about 12 hours or about 24 hours, orabout 168 hours, or about one month, and under gastric conditions orwhen a repetitive force of at least 500 grF or at least 800 gF or atleast 1000 gF or at least 2000 gF is applied. In the examples describedherein, the gastric retentive system is capable of substantiallymaintaining its size under application of at least about 500 gF, or atleast about 600 gF, or at least about 700 gF or at least about 800 gF orat least about 1000 gF or about 2000 gF applied every two hours. In theexamples disclosed herein, the GRDF may include a mechanical durabilityto maintain a size relevant for gastric retention over a period of timeof at least about 2, or at least about 3, or at least about 6, or atleast about 9, or at least about 12 or about 24 hours and under theapplication of a repetitive force ranging from about 400 gF to about3000 grF, in embodiments from about 400 gF to about 1000 gF. In theexamples described herein, the expanded state GRDF is capable ofresisting about 200 to about 600 gF over the full gastric retentiveperiod. In another example, the gastric retentive devices or systemsdescribed in detail provide a mechanical durability to maintain a sizerelevant for gastric retention, i.e., assembled with minimaldeformation/downsizing under the application of a repetitive force inany direction or position of at least about 500 gF or at least about 800gF or at least about 1000 gF or at least about 2000 gF over a period oftime of at least 2, 3, 6, 9, 12, 24, 48, 72 hours or up to a week, amonth or up to a couple of months. In this context, minimaldeformation/downsizing is considered about 20% or preferably about 10%change in largest dimension.

In the illustrated examples, the GRDF provides a gastric retentiveendpoint and/or opening of the closed circuit and/or disassembly of theGRDF and/or cleaving the connection between the erodible-insertcontaining arm and at least one of other arms. Changes in geometricand/or mechanical properties of the erodible insert compromises theclosed circuit and/or disassembles the body into its parts/units, theparts/units suitable for exiting the stomach via the gastric valvethereof.

In the examples described herein, the expanded state GRDF is capable ofmaintaining dimensional strength and strength under repeated forces overa period of time in the gastric environment and/or until about more than50%, 60%, 70%, 80% or 90% erosion of the erodible insert and/or untilabout 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% release of activeingredient. In some embodiments, the erosion of the erodible insert isat a rate similar to zero order preferably over 12 hours. Put anotherway the rate of erosion of the erodible insert is substantiallyconstant.

In an embodiment, % release of API (weight/weight=w/w) of the totalinitial API weight per day is about 12% to 22% as measured in rotatingbottle apparatus at 37° C. at 2.5 RPM having 400 mL, pH2 and Xanthan gum0.125 gr/L. In an embodiment, % RSD is less than about 80%, or less thanabout 60% or less than about 40% as measured in rotating bottleapparatus at 37° C. at 2.5 RPM having 400 mL, pH2 and Xanthan gum 0.125gr/L. In a preferred embodiment, disassembly/disengagement of the GRDFoccurs at a time point equivalent to more than 80%, more than 87%, morethan 90%, more than 95% or about 100% release of API.

In an embodiment, % release of API (w/w) of the total initial API weightper day is less than about 30%. In another embodiment, % release per dayis less than about 25%. In another embodiment, % release per day is lessthan about 23%. In another embodiment, % release per day is less thanabout 20%. In another embodiment, % release per day is less than about15%. In another embodiment, % release per day is about 12%. In otherexamples, % release per day is about from about 5% to about 30%. Inanother embodiment, % release per day is from about 10% to about 25%.

In another embodiment, % RSD of the % (w/w) release of API of the totalinitial API weight per day is less than about 80% as measured inrotating bottle apparatus at 37° C. at 2.5 RPM having 400 mL, pH2 andXanthan gum 0.125 gr/L. In another embodiment, % RSD is less than about60% as measured in rotating bottle apparatus at 37° C. at 2.5 RPM having400 mL, pH2 and Xanthan gum 0.125 gr/L. In another embodiment, % RSD isless than about 40% as measured in rotating bottle apparatus at 37° C.at 2.5 RPM having 400 mL, pH2 and Xanthan gum 0.125 gr/L.

In the examples described herein, the expanded state GRDF is capable ofbeing retained internal to a subject for extended periods of time beyondstandard oral extended release dosage forms. In some embodiments, GRDFis capable of gastric retention under light meal conditions for at least5 hours in 50% of subjects. In the examples described herein, theexpanded state GRDF is capable of gastric retention under light mealconditions for 5 hours in more than 50% of subjects. Assuming one canneutralize the effect of retention caused by the light meal, the GRDF iscapable of retention through at least one or preferably two cycles ofgastric housekeeping forces.

In the examples described herein, the expanded state GRDF is capable ofretention in a beagle dog stomach of at least 4 hours in about 50% ofdogs under fasted conditions. In the examples described herein, theexpanded GRDF is capable of retention in a beagle dog stomach of about 4hours in about 50% of dogs under fasted conditions.

In the examples described herein, the expanded state GRDF is capable ofgastric retention in a pig for about 4-36 hours under fasted conditions.In the examples described herein, the expanded state GRDF is capable ofgastric retention in a pig for at least 36 hours under fastedconditions. In the examples described herein, the expanded GRDF iscapable of retention in a pig stomach for at least 48 hours in about 83%of pigs under fasted conditions.

Optionally, in an additional example, any of GRDFs described orenvisioned herein may include an emergency release feature that allowsthe GRDF to pass through the pyloric valve for immediate removal fromthe stomach and gastrointestinal tract, if needed. An antidote or othertriggering mechanism may be employed to initiate the emergency releaseof the GRDF or gastric residence system. In one envisioned example, aGRDF of the present disclosure includes hinge assemblies (or any otherportion thereof) that are pH sensitive (for example sensitive to a pH5-5.5) such that under normal gastric conditions the system (or anyportion thereof) remains intact. However, if needed, the environmentalpH can be slightly increased (to within the above pH sensitive range orany other specified range) causing the mechanical integrity of the hingeassembly (or any portion thereof) to erode causing the hinge assembly todisassemble from one or both arms and pass through the pyloric valve forsubsequent evacuation.

EXPERIMENTAL EXAMPLES Example 1: Manufacture of a Gastric RetentiveSystem

Manufacture of a system as disclosed herein is described below,according to an aspect of this disclosure.

Example 1A—Manufacture of Extruded Beads

The extruded beads were prepared using hot melt extrusion technology.

“Formulation N”: cellulose acetate (400 g) and triacetin (100 grams).

“Formulation B”: HPMC AS HG (1600 grams), HPMC AS MG (400 grams), PEG3350 (44 grams) and dibutyl sebacate (176 grams).

Each of Formulation N and Formulation B was blended in a high shearmixer (DIOSNA P-25). The granules are then fed in twin-screw extruder(screw diameter 16 mm) at the rate of 1 kg/hr, screw speed of 150 RPM,melt temperature of 190° C. for Formulation N and 140° C. forFormulation B. The extrudate was cooled using air cooled conveyors andchopped into beads using a Varicut Pelletiser.

Example 1B Mold Manufacture

Molds of each of the GRDF parts were designed for use in injectionmolding technology. Extruded beads were fed into a Wittman EcoPower 55Ton Injection Molding Machine using injection parameters listed inTable 1. The parts obtained are illustrated in FIGS. 10 through 15 andFIGS. 19A-19C.

TABLE 1 Injection molding parameters Part Injected [shown in Barrel MoldInjection Hold Cycle FIGS. 10-15 and Temperature Temperature pressurepressure time FIG. 19A-19 C] [° C.] [° C.] [Bar] [Bar] [sec] Hingeassembly 170-215 65 1600 550 16-13 2021 (Formulation N) Hinge assembly170-220 65 1600 550 16-13 2020 (including an integral biasing member*)(Formulation N) Ramp 2006r ** 170-220 65 1600 700 16-13 (Formulation N)Arms 2001, 150-190 55-40 1400 750-700 23-18 2002 (Formulation B) Armsleeve, tube 150-190 60-40 2000 780-700 23-18 2003 (Formulation B) *Inan alternate example, the biasing member could be designed as a separatepart from the hinge assembly, made e.g. by injection molding. as anintegral part of the biasing member ** In an alternate example, ramp2006r could be designed as an integral part of the biasing member 2006and/or a hinge assembly, made e.g. by injection molding.

Example 1C: Mold Coating

The arms 2001, 2002 and 2003 were coated using an O'Hara LabCoat 15″machine. The dispersion formulation is presented in Table 2. The partswere coated using the following parameters: inlet temperature of 30° C.,exhaust temperature of 25° C., atomizing air pressure of 1.5 bars, sprayrate of 7-10 g/min and pan speed of 14-18 RPM. A coating weight gain of5.0% was applied to the parts. Curing step was done for half an hour atinlet temperature of 40° C.

TABLE 2 Enteric coating formulation Component Quantity [g] DibutylSebacate 27 Ferric oxid red 8 Talc extra fine 52 Eudragit ® S-100 312(Methacrylic Acid copolymer, Type B) Isopropyl Alcohol 3480 Acetone 870

Example 1D Erodible Insert Tablet Manufacturing

Erodible insert 2036 was made up of two types of tablets for a total offour units: two side tablets (2036S, FIG. 19D) for inclusion at eitherend of the sleeve or tube 2003 and two central tablets (2036L, FIG. 19D)placed in the center between the side tablets. Each punch was designedto fill the cavity of the GRDF. The tablets were produced using wetgranulation.

The formulation of the central tablets and side tablets are presented inTable 3. The intra-granular excipients were mixed in high shear mixer(Diosna P-10). The granulation solution (purified water) was added tothe high shear mixer during mixing. The obtained granulate was thendried using a fluid bed drier (FBD), milled using milling machine(Quadro 0.032″) and blended together with the extra-granular excipientsusing blender (Y-cone 5L).

TABLE 3 Tablet formulation 1 Quantity [g] Side tablet Central tabletComponent (2036S) (2036L) Intra-granular material Povidone (PVP K-90)156.8 276.0 Mannitol USP (PEARLITOL ® 9.5 412.8 200SD) Barium SulfateUSP 1237.5 1237.2 Ethocel ™ Premium 7 CPS 668.3 408.0 Granulationsolution (purified 210 210 water)* Extra-granular materials Mannitol USP(PEARLITOL ® 255.1 277.2 200SD) Magnesium Stearate 25.8 28.8 *evaporatedduring dryingTablet Formulation 1: The final blend was compressed into tablets usinga tablet press (Fette 102) (each central tab weighed 220 mg and eachside tablet weighed 160 mg).

Example 1E Mold Labelling

The 2001, 2003, 2020, 2021 were manually labelled with Barium sulphatefor detection in X-ray. Barium sulphate were manually placed on the2001, 2020, 2021 and 2003 (about 20-25 mg for each part) and then sealedusing a cellulose acetate solution 6.5% W/V in acetone.

All labelled parts were then dried at room temperature.

Example 1F Assembly of GRDF, FIG. 10

The ramp 2006 r was attached to the 2003 sleeve using 6% W/W celluloseacetate solution in acetone (100μ). Arms 2001 and 2002 were lubricatedusing Magnesium stearate powder. The insert erodible tablets 2036 wereplaced in the 2003 sleeve in the following order: one 2036S on each endand two 2036L in the centre. Hinges 2020 and 2021 were then manuallyconnected to respective arms 2001 and 2002. The final GRDF was stored inHDPE bottles with silica until dosing. Before in vivo dosing or in vitrotesting, assembled GRDF were folded and placed in a capsule 000 in anelongated state, as presented in FIG. 16A.

Example 2—In Vitro Characteristics

For the purposes of this example, in order to disassociate the effectsof the erodible insert, the hinges 2020 and 2021 were glued to opposingends of the 2003 arm [FIG. 10 ].

For the purposes of this example, the opening force is the minimum forceapplied by the GRDF to open from the compressed configuration, asillustrated as F1 in FIGS. 20A and 20B. In order to measure the minimumopening force, F1, the minimum weight applied at W on the compressedstructure (which was placed on a rigid surface), which resulted inslight opening was measured for both a comparative example and the testarticle described above, see FIG. 20A, 20B. Results are presented inTable 4.

For the purposes of this example, the rigidity of a device is a measureof a device's ability to resist change despite application of a force ofcompression, F2 in FIGS. 20C and 20D. F2 is calculated by measuring theminimum force which is applied for 30 seconds and which is required tocause a 10% decrease in the height of the expanded state gastricretentive at room temperature. Four systems were tested and results arepresented in Table 4.

Comparative device B: GRDF in FIGS. 20A and 20C* (additional details ofdesign are disclosed in PCT/US2015/033850, example 6-FIG. 18, 34B),using material from Formulation B

Comparative device N: GRDF in FIGS. 20A and 20C* (additional details ofdevice design are disclosed in PCT/US2015/033850, example 6-FIG. 18,34B), using material from, using material from Formulation N

GRDF B: GRS of Example 1—Formulation B GRDF N: GRS of Example1—Formulation N

TABLE 4 Results GRDF tested Comparative Comparative GRDF GRDF Forcedevice B device N B N Opening force F1 (grF) as 180 285 30 50 measuredby sensor Rigidity as measured by 700 850 2500 4000 minimum Force F2required to cause > 10% in height against (grF) as measured by sensorRatio of F1/F2: 0.257 0.335 0.012 0.013

Example 3—Beagle Dog Study Protocol

Five Beagle dogs [12-15 kg] were enrolled in the study. All animals wereevaluated over 3 days of repeat, sedated dosing after overnight fasting.The test article as described in Example 1 was endoscopically doseddirectly to the stomach cavity Immediately following dosing, ˜80 ml ofwater (room temp) was administered via the endoscope directly to thestomach cavity. Approximately 5 minutes later, dosing fluoroscopy wasperformed to evaluate GRDF location and condition (open or closed). Ifthe GRDF had not opened, an additional fluoroscopy evaluation wasperformed at ˜15 minutes post-dosing. The following fluoroscopy followup schedule was employed after the first and final dosing: 4 h, 8 h, 12h, 24 h, 36 h and 48 h for a total of 5 days±2 days following the finaldosing or until the test sample left the stomach cavity. Approximately 5hours following a dose, the animals were fed a ˜150 kcal meal. Prior tofasting, for a minimum of 12 hours, the animals were provided a meal ofat least ˜300 kcal or normal PM rations if exceeding 300 kcal.

On ˜Day 7 the animals underwent final fluoroscopy imaging.

Safety Results:

All animals were generally healthy throughout the duration of the studywithout gastrointestinal irritation and/or injury observed in the GI.There was no premature emptying of encapsulated test product from thestomach. Fecal Occult Blood Test (FOBT) was negative prior to and at endof the study. Feces was collected at least once a day, and the collectedfeces was examined for remnants of the test article; which were assessedfor the physical state and then photographed, collected, and returned tothe Sponsor after the end of the study. No abnormal feces were noted.The biodegradable components of the test article were noted to be verysoft or almost completely eroded.

Results:

TABLE 5 Results of Dog Study Parameter Dogs Meal condition Fasted %Gastric retentive system expanded 50% (5/10) at 4 hr* and assembled instomach 0% (0/10) at 8-36 hr Premature emptying from stomach None intothe intestine of expanded form % Gastric retentive system 50% (5/10) at4 hr* disassembled in GI (prior to exiting 60% (6/10) at 8 hr animal)33% (5/15) at 12 hr 13% (2/15) at 24 hr 10% (1/10) at 36 hr *based on 2or 3 doses

Example 4—Pig Study Protocol

Twelve Yorkshire pigs were divided into two treatment groups, test andcontrol, with a total of 6 animals (3 male, 3 female) evaluated over 5days of repeat, sedated dosing after overnight fasting. The test articleas described in Example 1 was dosed via gastric tube directly to thestomach cavity Immediately following dosing, ˜200-250 ml water (roomtemperature) was administered via the gastric tube directly to thestomach cavity. Approximately 5 minutes later, the dosing fluoroscopywas performed to evaluate device location and condition (open orclosed). The fluoroscopy follow up schedule was employed after the firstand final dosing: 4 h, 8 h, 12 h, 24 h (immediately following 2nd dose),36 h, and 48 h (immediately following 3rd dose). Approximately 5 hoursafter a dose, the animals were fed normal AM feed rations. Prior tofasting, for a minimum of 12 hours, the animals were provided withnormal PM feed rations.

Feces monitoring and collection occurred at least twice daily during thein-life duration. Collected feces were examined for test articleremnants, and continued until either all remnants were recovered or theanimal was terminated.

On ˜Day 7 the animals underwent final fluoroscopy imaging and euthanizedfor a complete necropsy. Tissues were collected for further histologicalanalysis.

TABLE 6 Results of Pig Study Parameter Pigs Meal condition Fasted %Gastric retentive system expanded and 100% (6/6) at 4-36 hr* assembledin stomach 83% (5/6) at 48 hr Premature emptying from stomach into Noneintestine of expanded form % Gastric retentive system disassembled in 0%(0/6) at 4-36 hr* GI (prior to exiting animal) 17% (1/6) at 48 hr *basedon first dose

Example 5—Human Study

A single centre, single dose, two-cohort, open-label study was approvedby the IRB and conducted according to GCP with informed healthy subjects(males and females, aged 50-70 years, total n=12). Cohort 1 (n=4) wentthrough a single period under light meal condition, Cohort 2 (n=8) had arandomized 2-period, 2-way-cross-over design with 2 different mealconditions (i.e. light and moderate meal).

After an overnight fast of >10 hrs, subjects had to complete either alight caloric breakfast (130 kcal, 21% fat) within 20 min or a moderatecaloric breakfast (552 kcal, 48% fat) within 45 min, depending on therespective Cohort/Period Immediately after breakfast (at 20 or 45 minafter start of light or moderate fat breakfast, respectively), a singledose of the test product described in Example 1 was administered orallyto each subject with a glass of water.

In light meal test arm, a lunch (500 kcal) and a dinner were served at 5hrs and 10 hrs post dose (herein “pd”), respectively. In periods undermoderate meal conditions, a lunch (862 kcal) and a dinner were served at4 hrs and 10 hrs pd, respectively.

Serial X-Ray Imaging and/or Fluoroscopy Scans were performed pd toconfirm and document anatomical location and state of test product X-rayimages were conducted with a fluoroscopy device at 0.167, 5, 8, and 10hrs pd. Fluoroscopy only was performed at 4, 7 and additionally at 15hrs pd if gastric retention (GR) was demonstrated at 10 hrs pd.

Results

Capabilities of expanded and assembled test product: The number ofsubjects with test product in expanded and assembled state in stomachand intestine are shown in Table 7.

The test products, in expanded and assembled state, were capable ofenduring the conditions of healthy subjects' stomach under differentmeal conditions after a single dose. FIGS. 18A-18C are a series of x-rayimaging photographs taken after 10 minutes (FIG. 18A), 4 hours (FIG.18B), and 24 hours (FIG. 18C) post swallowing.

TABLE 7 Results of Human Study Number of subjects with assembled ordownsized test product over time Light meal condition [n=12] Moderatemeal condition [n=8] Test Expanded Expanded Expanded Expanded product/state in state in state in state in Time point stomach intestine stomachintestine 10 min 12 0 8 0  4 hrs 6 1 3 1  5 hrs 6 1 3 1  7 hrs 4 1 1 1 8 hrs 3 0 1 1 10 hrs 2 0 1 1 15 hrs 1 0 1 1

Safety and tolerability after a single dose to healthy subjects wereacceptable and no serious adverse events occurred. All GRDFs eventuallydownsized for safe passage through the downstream intestinal tract.

Example 6—Manufacture of a GRDF for Extended Oral Release

Manufacture of a GRDF as disclosed herein is described below, accordingto an aspect of this disclosure.

Example 6A—Manufacture of Extruded Beads

The extruded beads were prepared using hot melt extrusion technology.

“Formulation N”: cellulose acetate (4000 g) and triacetin (1000 grams):Formulation N was blended in a high shear mixer (DIOSNA P-25). Thegranules are then fed in twin-screw extruder (screw diameter 16 mm) atthe rate of 1 kg/hr, screw speed of 150 RPM, melt temperature of 190° C.for Formulation N. The extrudate was cooled using air cooled conveyorsand chopped into beads using a Varicut Pelletiser.

Example 6B Mold Manufacture

Molds of each of the GRDF parts were designed for use in injectionmolding technology. Extruded beads were fed into a Wittman EcoPower 55Ton Injection Molding Machine using injection parameters listed inTable 1. The obtained parts are illustrated in FIGS. 10 through 15 ,FIGS. 19A-19C and FIG. 21 .

TABLE 8 Injection molding parameters Part Injected [shown in FIGS. 10-15Barrel Mold and Temper- Temper- Injection Hold Cycle FIG. 19A-19 atureature pressure pressure time C, FIG. 21] [° C.] [° C.] [Bar] [Bar] [sec]Hinge assembly 170-215 65 1600 550 16-13 2021* (Formulation N) Hingeassembly 170-220 65 1600 550 16-13 2020* (including an integral biasingmember**) (Formulation N) Ramp 2006r *** 170-220 65 1600 700 16-13(Formulation N) Arms 2001, 2002 170-220 65-50 1000-1600 700-850 23-18(Formulation N) Arm sleeve, tube 150-190 50-40 2000-2500 1100-1300 22-172003 (Formulation N) *width of shoulder of 2020a and 2021a was minimizedto 180 μm **In an alternate example, the biasing member could bedesigned as a separate part from the hinge assembly, made e.g. byinjection molding. *** In an alternate example, ramp 2006r could bedesigned as an integral part of the biasing member 2006 and or a hingeassembly, made e.g. by injection molding.

Example 6C(a): Tablet Manufacturing

In a particular example, erodible insert 2036 was made up of two typesof tablets for a total of four units: two side tablets (2036S, FIG. 11,19D, 22 ) for inclusion at either end of the sleeve or tube 2003 and twocentral tablets (2036L, FIG. 11, 19D, 22 ) placed between the sidetablets. Each punch was designed to fill the cavity of the GRDF. Thetablets were produced using wet granulation.

Two alternative formulations of the central tablets and two alternativeformulations of side tablets are presented in Table 9. Theintra-granular excipients were mixed in high shear mixer (Diosna P-10).The granulation solution (purified water) was added to the high shearmixer during mixing. The obtained granulate was then dried using a fluidbed drier (FBD), milled using milling machine (Quadro 0.032″) andblended together with the extra-granular excipients using blender(Y-cone 5L).

TABLE 9 Tablets’ formulations Quantity [mg/tab] Side Side CentralCentral tablet tablet tablet tablet (2036S) (2036S) (2036L) (2036L) 2.2%3% 2.2% 4% Methocel ® Methocel ® Methocel ® Methocel ® ComponentR-15628S R-15641S R-15628L R-15642L Intra-granular materials-units in mg(% per tablet) Levodopa 75 (56%) 75.7 (56%)   101 (56%)  101 (56%) Carbidopa (C) 19.7 (14.7%) 19.6 (14.5%) 26.3 (14.6%) 14.6%) Entacapone18.2 (13.6%) 18.2 (13.5%) 24.3 (13.5%) 24.3 (13.5%) Methocel ® 3 4.1 47.3 (HPMC E4M) Starch 6 6 8 8 Granulation solution (purified water)*Extra-granular materials Magnesium 1.2 1.2 1.6 1.6 stearate NFMicrocrystalline 8.6 7.4 11.5 7.8 cellulose (Avicel ®) Sodium starch 2.42.7 3.2 3.8 glycolate Total weight 134.1 134.9 179.9 180 % API in 84.284.1 84.3 84.2 formulation *evaporation during drying

The final blend was compressed into tablets using a tablet press (Fette102) (each central tab weighed 180 mg and each side tablet weighed 135mg).

Example 6C(b): Tablet Coating

In an attempt to control the direction and the rate of erosion of theerodible insert, the tablets were partially coated with enteric coating.The extent and placement of the coating allowed control of the locationand area of exposure of the tablets to gastric fluid. In the currentexample, gastric fluid penetration was aimed to occur at the centralopenings of sleeve 2003, resulting in directional erosion from thecentre towards the two ends of the sleeve: erosion of the centraltablets (2036L) first, followed by erosion of the side tablets (2036S).It's likely that premature erosion of the side tablets would result inpremature disengagement of the hinge assembly and disassembly of theGRDF before the central tablets are eroded. Coating of certain surfaceson the tablets and particularly the side tablets 2036S is aimed toprevent the premature exposure of the side tablets 2036S to gastricfluid.

The two side tablets 2036S, and two central tablets 2036L (FIG. 11, 19D,22 ,) were coated with the enteric coating formulation as describedbelow and in Table 10, to reach about 5% weight gain, based on tabletweight.

Enteric Coating Formulation Preparation:

Part I: Eudragit S® was mixed in acetone and IPA solutions untildissolved. Part II: In parallel, dibutyl sebacate, talc and sieved col.ferric oxide (60 mesh) were added to the acetone and isopropyl solutionmixture and mixed with a Silverson mixer homogenizer. After thoroughmixing, the dispersion was sieved through a 100 mesh. The result wasthen combined with the Eudragit S® solution of Part I and mixing wascontinued until coating.

TABLE 10 Enteric coating formulation Raw Materials weight * (gr) Part 1Eudragit S-100 ® (METH.ACID&METH. 312 Acetone NF/PH.EUR 630 IsopropylAlcohol USP 2520 Part II Ferric oxide red col. NF. 8.15 Talc USP ExtraFine 52.5 Dibutyl Sebacate NF 27.3 Acetone NF/PH.EUR 240 IsopropylAlcohol USP 960 Weight (in excess) 4749.95 * weight in excess to coat atleast 550 tablets coating

Coating was performed in a vector coater coating machine with thefollowing settings: inlet temperature: 32-30° C., outlet temperature:25° C. (target), drum speed: 14-18 RPM, nozzle pressure: 1300 PSI, sprayrate: 8-12 mL/min.

At 5% tablet weight gain, curing was performed with an inlet setting of40° C. for about 30 min. The coating is illustrated by the bolded linesof 2036S and 2036L, FIG. 22 .

Coating was then removed from the sides of the tablets which form aninterface between the tablets (FIG. 22 ) via filing the coating layer.In addition, uncoated areas were formed to overlap with central openingsin the arm sleeve, as illustrated in FIG. 22 .

Example 6D—Assembly of GRDF

The ramp 2006 r was added to the 2003 arm sleeve using the celluloseacetate solution described in Example 1A. Arms 2001 and 2002 werelubricated using Magnesium stearate powder. The tablets were placed inthe 2003 sleeve in the following order: one 2036S on each end and two2036L in the centre, wherein filed faces of each tablet were in contactwith one another. Hinge assemblies 2020 and 2021 were then manuallyconnected to respective arms 2001 and 2002 using the cellulose acetatesolution (6% w/w solution of cellulose acetate in acetone). The finalGRDF was stored in HDPE bottles with silica until testing or dosing.Before in vitro testing, assembled GRDFs were folded and placed in acapsule (size 000) in an elongated state, as presented in FIG. 16A.

Example 7: In Vitro Dissolution of Actives from GRDFs: ComparingActives, Tablet Formulations and Sum Exposure Area

The dissolution of API over time was evaluated using a rotating bottleapparatus at 37° C. at 2.5 RPM having 400 mL, pH2 and Xanthan gum 0.125gr/L.

The rate of release of active was tested for the GRDFs in example 6,having varying erodible tablet formulations as presented in Tables 9 and11, as well as varying sum exposure areas resulting from variation inopening sizes in the sleeve as shown in FIG. 21 and Table 11 (sumexposure area) as well as tablet coating as presented in Table 11 (RHoles exposure status). The following parameters calculated: average %release per day, standard deviation and relative standard deviation(standard deviation divided by average=% RSD).

Example 7a: In Vitro Dissolution of Entacapone from GRDF

Percent dissolution of entacapone was calculated at the following timepoints: 0.0, 5.0, 21.5, 29.0, 45.5, 69.0, 94.5, 98.0, 120.0 and 168.0hours. Test conditions, percent active release at disassembly and timeof disassembly are presented in Table 11. The mean release of API perday, stdev (% release per day) and % RSD are presented in Table 12.Accumulated % release of Entacapone over time is shown in FIG. 23 and inTable 13.

Examples 7b, 7c and 7d: In Vitro Dissolution of Levodopa and Carbidopafrom GRDF

Percent dissolution was calculated at the following time points: 0.0,16.0, 23.0, 41.0, 47.0, 64.0, 71.0, 87.0, 95.0, 113.0, 158.0 and 168.0hours. In an attempt to simulate forces acting on a GRDF in vivo, fivetests per day were conducted, wherein a weight of 600 gr was applied ateach of the three apices of the triangular GRDF for 2 seconds×10 timesper test.

Test conditions, percent active release at disassembly and time ofdisassembly are presented in Table 11. The mean release of API per day,stdev (% release per day) and % RSD are presented in Table 12.Accumulated % release of Levodopa and Carbidopa over time is presentedis in FIG. 24 and in Table 14.

TABLE 11 GRDF assembly configuration. timing of disassembly anddissolution characteristics 2003 sleeve R Holes type exposure Centralbased on Sum status (fully % API tablet Side R hole exposure exposed,release at [203 6L] tablet size in area partially point of Timing ofExample Formulation [2036S] FIG. 21 (mm²) sealed)* disassemblydisassembly 7a R-15628L R-15628S M 20.4 Partially not not sealedmeasured measured 7b R-15642L R-15641S L 59.8 Fully Approximat  112 hrexposed ely 100% (at least 95%) 7c R-15642L R-15628S M 40.7 FullyApproximat  158 hr exposed ely 98% (>95%) 7d R-15642L R-15628S S 15.5Partially At least 80% >200 hr sealed *A partially sealed status isobtained when tablet/erodible insert surface areas facing at least someof the “R holes” (FIG. 21) are coated by an enteric coating. A fullyexposed status is obtained when all the tablet/erodible insert surfaceareas facing “R holes” are uncoated.

TABLE 12 % API release/day, mean release/day, Stdev/day and % RSD forexamples 7a-7d Day Example 7a Example 7b Example 7c Example 7d 1 29.820.9 11.2 3.5 2 24.4 39.5 37.8 20.9 3 19.3 18.7 19.8 25.2 4 19.6 16.810.0 15.9 5 21.1 12.2 10.6 11.3 6 6.2 5.8 7 7.1 6.1 Mean (% 21.1 21.614.7 127 release/day) Stdev (% 6.56 10.50 11.10 827 release/day) % RSD31.17 48.52 75.66 65.24

TABLE 13 accumulated release of active in example 7a Day % 0.0 0.0 0.926.7 1.9 51.1 2.9 70.0 3.9 90.9 5.0 103.8

TABLE 14 accumulated release of active in examples 7b-7d Example 7bExample 7c Example 7d (timed disassembly (timed disassembly (timeddisassembly > about 4.7 days) about 6.6 days) 8.3 days) Day % % % 0.00.0 0.0 0.0 1.0 20.1 10.8 3.4 2.0 59.7 48.6 24.3 3.0 78.3 68.4 49.4 4.095.1 78.4 65.3 4.7 104.3 86.3 73.8 6.6 98.0 84.7 7.0 87.3

As presented in Tables 11-14, the GRDF of the present invention wasable, in the simulated model, to retain its integrity (equivalent toretention in the stomach) for 112 hours (about 4.7 days) 158 hours(about 6.6 days) and more than 200 hours (more than about 8.3 days).Therefore, the ability of the GRDF of the present invention to retain inthe stomach for about 4.7 days, about 6.6 days and more than 8.3 dayswas demonstrated.

Percent release of API (weight/weight=w/w) of the total initial APIweight per day was about 10% to 25%, or about 12% to 22% (or less thanabout 30%, or less than about 25%, or less than about 20%, or less thanabout 15%, or about 12%).

Percent RSD of the % release of active pharmaceutical ingredient (API)of the total API per day was about 31% as measured in rotating bottleapparatus at 37° C. at 2.5 RPM having 400 mL, pH2 and Xanthan gum 0.125gr/L in example 7a. In example 7b, % RSD was about 49% as measured inrotating bottle apparatus at 37° C. at 2.5 RPM having 400 mL, pH2 andXanthan gum 0.125 gr/L. In example 7c, % RSD about 76% as measured inrotating bottle apparatus at 37° C. at 2.5 RPM having 400 mL, pH2 andXanthan gum 0.125 gr/L. In example 7c, % RSD was about 65% as measuredin rotating bottle apparatus at 37° C. at 2.5 RPM having 400 mL, pH2 andXanthan gum 0.125 gr/L.

Percent RSD (w/w) was less than about 80%, or less than about 70% orless than about 50% or less than about 40% or less than about 35% asmeasured in rotating bottle apparatus at 37° C. at 2.5 RPM having 400mL, pH2 and Xanthan gum 0.125 gr/L.

The time of disassembly in examples 7b-7d seemed to be connected to thesum exposure area. Using the indicated formulations, the smallest sumexposure area tested (15.5 mm2) allowed more than about 8.3 days ofmaintaining of the integrity of the GRDF, simulating retention in thestomach. Sum exposure area of 59.8 mm2 allowed about 4.7 days of GRDFintegrity the described model, simulating retention in the stomach. Sumexposure area of 40.7 mm2 allowed about 6.6 days of GRDF integrity,simulating retention in the stomach. Mechanical disassembly of the GRDFoccurred at a time point equivalent to at least 70% (w/w), at least 80%(w/w), at least 87% (w/w), at least 95% (w/w), at least 98% (w/w) orabout 100% API release from the erodible insert. As the dispersion ofAPI in the erodible insert in this example was generally homogenous, isshould be assumed that API release was correlated, similar or verysimilar to the % erosion of the erodible insert.

Therefore, enteric coating of the tablets, as well as adjusting thelocation and size of the openings in the shell of the mediating arm,improved the control over the rate of erosion of the erodible insert,and the GRDF mechanical disassembly. Alignment of the uncoated areas onthe erodible insert with the openings in the shell of the mediating arm,defined specific overlapping areas which were exclusively exposed togastric fluid, and provided extended retention in the stomach forperiods of time longer than had been demonstrated before.

To note, coating of the tablets has advantages for the manufacturingprocess as well, such as allowing the use of standard formulatingmethods (e.g. tableting methods) to produce the insert tablet/s or otherdosage forms, as well as the free choice of APIs and excipientsregardless of sensitivity to heat, pH, etc. In addition, physicalseparation between tablets is enabled using optionally separate coatingof each tablet, allowing the inclusion of adjacent tablets containingAPIs and/or excipients that are chemically or physically incompatible.To note, each tablet or other dosage form forming the erodible insertcan include one or more than one APIs.

Example 8: Self-Priming GRDF

In some embodiments, priming of the biasing member as presented in FIG.16 has the limitation that it should be conducted prior toadministration to the subject. A mechanism is presented which allowspreservation of the GRDF in a compressed and primed state, e.g. in thecapsule, for an extended shelf-life.

FIGS. 25A-B Illustrate an alternative configuration to the GRDFconfiguration as presented in FIG. 16 . In the compressed configuration,portion 2006 c of the biasing member extends over arm 2003 in a similarmanner to the embodiment described with respect to FIGS. 1-15 above. Asecond portion 2006 d of the biasing member is angled with respect tothe first portion 2006 c of the biasing member and extends into hingeassembly 2020. A hook is connected to portion 2006 d of biasing memberand another hook is connected to hinge assembly 2020. An elastic elementexemplified here by a band as presented in FIG. 25 , is stretchedbetween these two hooks. The elastic element is made of materials havingelastic properties such that when the band is stretched, the bandmaintains its elastic properties with minimal to no plastic deformation,also maintaining the moments needed to unfold the GRDF. Adequatematerials to be used in the elastic element, e.g. a band are exemplifiedby silicon rubber, which mechanical properties are described in Table15. Other materials with mechanical properties similar to propertiesdescribed in Table 15, and/or having the quality of maintaining elasticproperties upon stretch with minimal to no plastic deformation couldalso be used, as will be appreciated by the person skilled in the art.

While the GRDF is in a compressed configuration, the GRDF is maintainedin a cocked/primed state (FIG. 25A). The stretching of the band in thisconfiguration exerts a momentum on portion 2006 d of the biasing member,creating a momentum of 2006 c on arms 2001 and 2002 to unfold the GRDFinto the expanded configuration, while the external capsule 2030 resiststhis momentum and keeps the GRDF in its compressed configuration. Oncecapsule 2030 dissolves, the momenta exerted on portions 2006 d and 2006c of the biasing member leads to unfolding of the GRDF.

A feasibility of the principle of the self-priming GRDF was tested aspresented in FIG. 26 . A 1.5 mm slice of silicon rubber tube having a 5mm external diameter and a 2 mm internal diameter and mechanicalproperties as described in Table 15 was used as elastic band. The GRDFwas placed in capsule 000 in a compressed configuration for two months.After two months the capsule was extracted, resulting in GRDF unfoldedinto the expanded state within less than 2 sec. The biasing membermaintained its original structure with no observed deformation. Theresults of the experiment demonstrate the feasibility of the newnon-priming mechanism of the present invention to maintain the primingstatus over elongated time periods, obviating the need to prime the GRDFjust prior to administration.

TABLE 15 Silicone rubber mechanical properties Test unit ASTM std. no.result 1 color — clear 2 hardness D2240 55-65 3 tensile strength D412 8.5 (minimum) 4 elongation D412  500 (minimum) 5 Tear resistance D624  25 (minimum)

Thus a GRDF having improved gastric retention over previously knownGRDFs has been described. In an embodiment, the GRDF comprises a bodyincluding at least two arms. In an embodiment, the body is configured totransform between a collapsed configuration for ingestion, an expandedconfiguration for retention within the stomach and a disassembledconfiguration, wherein after a predetermined time period has elapsed,the GRDF mechanically disassembles into at least two parts such thateach of the disassembled parts of the GRDF is sized for exiting thestomach. In an embodiment, the GRDF further comprises an erodible insertcomprising a therapeutic agent, a diagnostic agent, an electronicaldevice, or any combination thereof. In an embodiment, the erodibleinsert is an elongate erodible insert having two opposing ends. In anembodiment, erosion of the erodible insert is configured to release thetherapeutic agent, diagnostic agent, electronic device or combinationthereof into the gastric fluid. In an embodiment the GRDF is maintainedin a collapsed configuration by a retainer. In an embodiment, theretainer is a capsule, a wrapper, or band surrounding the GRDF. In anembodiment, transformation of the body of the GRDF from a compressed toan extended configuration is induced by erosion of the retainer. In anembodiment, the GRDF includes a biasing member configured to bias theGRDF into the expanded configuration, for example following erosion ofthe retainer. In an embodiment, the GRDF disassembly is induced by atleast partial erosion of the erodible insert. In an embodiment, the GRDFdisassembly is induced by erosion of at least 70%, at least 80%, atleast 87%, at least 90%, at least 95%, at least 98% or about 100% of theerodible insert. In an embodiment, the GRDF disassembly is induced bythe disengagement of at least one hinge assembly from at least one arm.In an embodiment, the body includes three arms and two hinge assemblies.

In an embodiment, the GRDF is adapted for stomach retention for at least3 days, at least 4 days, at least 5 days, at least 6 days least 7 daysor at least 8 days. In an embodiment, at least a portion of at least onearm of the at least two arms forms a sleeve, tube or shell. In anembodiment, the sleeve, tube or shell comprises a cavity. In anembodiment, the cavity is configured to house an erodible insert. In anembodiment, the erodible insert is contained in the cavity comprised inthe sleeve, tube or shell of the at least one arm. In an embodiment, atleast one opening is present or formed in the sleeve, tube or shell ofthe at least one arm housing the erodible insert. In an embodiment, theerodible insert is partially coated with a gastric-non-erodible coating.In an embodiment, at least one uncoated area of the erodible insertoverlaps, or faces at least one opening in the sleeve of an arm housingthe erodible insert, thus defining at least one “overlapping area” whichis exposed to gastric fluid. In an embodiment, the erodible insert isexclusively exposed to gastric fluid at the at least on overlappingarea. In an embodiment, the GRDF of the present invention includes oneoverlapping area. In an embodiment, the GRDF of the present inventionincludes more than one overlapping areas. In an embodiment, the sum areaof the overlapping areas is less than 59.8 mm², or less than 40.7 mm²,or less than 15.5 mm². In an embodiment, the sum area of the overlappingareas is less than 59.8 mm² and the gastric retention time is at least4.6 days, or the sum area of the overlapping areas is less than 40.7 mm²and the gastric retention time is at least 6.6 days, or the sum area ofthe overlapping areas is less than 15.5 mm² and the gastric retentiontime is at least 8.3 days. It is to be noted that the sum exposure areamay be adjusted by the person skilled in the art in order to controlerosion of the erodible insert and GRDF retention time in the stomach.In an embodiment, the at least one overlapping area is presentequidistant from both ends of the erodible insert. In an embodiment, theat least one overlapping area is located closer to one end of theerodible insert than to the opposing end. In an embodiment, the erosionis bidirectional towards both ends of the erodible insert and/or towardsthe hinge assemblies.

In an embodiment, release of the API as well as mechanical disassemblyof the GRDF of the present invention are exclusively induced by erosionof the erodible insert, leading to disengagement of at least one hingeassembly from at least one arm. According to this embodiment, release ofthe API and mechanical disassembly of the GRDF to parts sized forexiting the stomach are not induced by erosion of the body of the GRDF,including e.g. any of the arms or the hinge assemblies. In addition, theAPI does not diffuse from the GRDF per se. In an embodiment, the API isnot included in any part of the body of the GRDF. In this embodiment,the API is exclusively included in the erodible insert. In anembodiment, the body of the GRDF, e.g. all of the arms or the hingeassemblies, do not degrade in the stomach, and do not substantiallychange their size, shape and/or weight upon exposure to gastric fluid.In an embodiment, the body of the GRDF is not eroded at GRDFdisassembly. In an embodiment, the body consists of gastric-non-erodiblematerials. In an embodiment, the at least two arms and/or the at leastone hinge assembly consist of gastric-non-erodible materials. In anembodiment, the three arms and the two hinge assemblies consist ofgastric-non-erodible materials. In an embodiment, the body of the GRDFand/or the at least two arms and the at least one hinge assembly consistof at least one gastric-non-erodible polymer. In a further embodiment,the at least one gastric-non-erodible polymer is a cellulose ester. In afurther embodiment, the cellulose ester is selected from celluloseacetate, cellulose butyrate, or a combination thereof. In a furtherembodiment, the material composing the body of the GRDF does notcomprise a therapeutic agent, i.e. the API is present within one or moreerodible insert, which is housed in a cavity in at least one arm of theGRDF. In an embodiment, the at least two arms and/or the at least onehinge assembly are coated with a gastric-non-erodible coating.

In an embodiment, the erodible insert is housed in at least one arm ofthe body of the GRDF, wherein only certain surfaces of the erodibleinsert are exposed to the gastric environment. In an embodiment, theerodible insert is not fastened to the body of the GRDF by any physicalmeasure selected from gluing or tethering. In an embodiment, theerodible insert is not fastened to the at least two arms by any physicalmeasure selected from gluing or tethering. In an embodiment, the atleast two arms and/or the at least one hinge assembly do not comprise anelastomer. In an embodiment, the at least two arms and/or the at leastone hinge assembly comprise at least one polymer. In an embodiment, theat least one polymer comprised in the at least two arms and/or in the atleast one hinge assembly is a gastric-non-erodible polymer. In anembodiment, the at least two arms and/or the at least one hinge assemblyconsist of gastric-non-erodible materials, e.g. low-pH-resistantpolymer(s). In an embodiment, the body of the GRDF consists ofgastric-non-erodible materials, e.g. low-pH-resistant polymer(s). In anembodiment, the at least two arms and the at least one hinge assemblyare substantially not eroded during GRDF retention and GRDF disassembly.

The present invention also includes a manual mechanism for priming ofthe GRDF for administration to the patient, which obviates the need fora separate device for cocking/priming the biasing member before use. Insome embodiments said priming is horizontal priming. In an embodiment,the mechanism includes

-   -   a) a GRDF which includes a body including at least two arms, the        body configured to transform between a collapsed configuration        for ingestion, an expanded configuration for retention within        the stomach and a disassembled configuration, wherein after a        predetermined time period has elapsed, the GRDF disassembles        into at least two parts such that each of the disassembled parts        of the GRDF is sized for exiting the stomach;    -   b) an erodible insert comprising a therapeutic agent, a        diagnostic agent, an electronical device, or a combination        thereof,    -   c) a biasing member having a first portion and a second portion,    -   d) a retainer configured to house the GRDF for ingestion,        wherein the retainer has a main portion and a closing portion,        wherein the retainer is configured to retain the GRDF in the        collapsed configuration, and    -   e) a priming member extending from an interior side of said        closing portion.        In an embodiment, the GRDF disassembly into the at least two        parts is a mechanical disassembly. In an embodiment, the        mechanism is used by placing said GRDF in the main portion,        wherein the GRDF is in a collapsed configuration, attaching the        closing portion to the main portion of the retainer and pressing        the closing portion in the direction of the main body so that        the priming member pushes said first portion of the biasing        member to a position perpendicular to said second portion of the        priming biasing, thereby priming the GRDF for use. In an        embodiment, the manual priming mechanism as described further        comprises a retaining element. In a further embodiment, the        retaining element retains the biasing member in a primed state        until dissolution of the retainer. In an embodiment, the        retainer is a capsule.

The present invention further includes a mechanism for self-cocking ofthe GRDF, obviating the need to manually cock/prime the GRDF just priorto administration. In an embodiment, self-cocking/priming mechanismincludes a GRDF which includes a body including at least two arms, thebody configured to transform between a collapsed configuration foringestion, an expanded configuration for retention within the stomachand a disassembled configuration, wherein after a predetermined timeperiod has elapsed, the GRDF disassembles into at least two parts suchthat each of the disassembled parts of the GRDF is sized for exiting thestomach, an erodible insert comprising a therapeutic agent, a diagnosticagent, an electronical device, or a combination thereof, a biasingmember, and at least one hinge assembly, wherein the biasing member andthe at least one hinge assembly are connected by an elastic element. Inan embodiment, the elastic element is stretched when the GRDF ismaintained in a collapsed configuration. In an embodiment, the elasticelement maintains its elastic properties with minimal to no plasticdeformation for at least 2 months, for at least 4 months, for at leastone year, or for at least 2 years. In an embodiment, the elastic elementis made of silicone rubber. In an embodiment, the elastic element has aminimal tensile strength of 8.5 GPa and minimal elongation of 500% astested in ASTM D412. In an embodiment, the elastic element further hashardness of 40-80 shore A as tested in D2240 ASTM test. In anembodiment, the GRDF disassembly into the at least two parts is amechanical disassembly. While several embodiments of the disclosure havebeen shown in the drawings, it is not intended that the disclosure belimited thereto, as it is intended that the disclosure be as broad inscope as the art will allow and that the specification be read likewise.Therefore, the above description should not be construed as limiting,but merely as exemplifications of particular embodiments. Those skilledin the art will envision other modifications within the scope and spiritof the claims appended hereto.

What is claimed:
 1. A gastroretentive dosage form (GRDF) for extendedretention in a human stomach, comprising: a. a body comprising at leasttwo arms, the body configured to transform between a collapsedconfiguration for ingestion, an expanded configuration for retentionwithin the stomach and a disassembled configuration wherein after apredetermined time period has elapsed, the GRDF disassembles into atleast two parts such that each of the disassembled parts of the GRDF issized for exiting the stomach; and b. an erodible insert comprising atherapeutic agent, a diagnostic agent, an electronical device, or acombination thereof; wherein at least a portion of at least one arm ofsaid at least two arms forms a sleeve, tube or shell, wherein saidsleeve, tube or shell of said at least one arm comprises a cavity and atleast one opening, wherein said at least one opening is configured toexpose said erodible insert housed in said cavity to gastric fluid;wherein said erodible insert is housed in said cavity; and wherein anuncoated surface area on said erodible insert overlaps with said atleast one opening in said sleeve, tube or shell, thereby defining atleast one overlapping area exposed to gastric fluid, and wherein a sumarea of said at least one overlapping area is less than 59.8 mm², orless than 40.7 mm², or less than 15.5 mm².
 2. The GRDF according toclaim 1, wherein a sum area of the at least one overlapping area isabout 15.5 to about 59.8 mm².
 3. The GRDF according to claim 1, whereinthe body comprises at least three arms.
 4. The GRDF according to claim1, wherein the GRDF mechanically disassembles into at least two partssuch that each of the disassembled parts of the GRDF is sized forexiting the stomach.
 5. The GRDF according to claim 1, wherein the bodyfurther comprises at least one hinge assembly configured to disengagefrom at least one arm upon at least partial erosion of the erodibleinsert.
 6. The GRDF according to claim 1, wherein the disassembledconfiguration is induced by at least partial erosion of the erodibleinsert.
 7. The GRDF according to claim 1, wherein the at least partialerosion of the erodible insert is at least 70% (w/w), at least 80%(w/w), at least 87% (w/w), at least 90% (w/w), at least 95% (w/w), atleast 98% (w/w) or about 100% (w/w) erosion of the initial weight of theerodible insert.
 8. The GRDF according to claim 1, wherein the GRDFincludes two or more overlapping areas.
 9. The GRDF according to claim1, wherein the at least one overlapping area is equidistant from bothends of the erodible insert or ends of the arm.
 10. The GRDF accordingto claim 1, wherein the at least one overlapping area is located closerto one end of the erodible insert than to the other end of the erodibleinsert.
 11. The GRDF according to claim 1, wherein erosion of theerodible insert progresses bidirectionally from the overlapping area toboth ends of the erodible insert.
 12. The GRDF according to claim 1,wherein the erodible insert comprises more than one therapeutic agent.